Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2017

Open Access 01-12-2017 | Review

Epigenetics in cancer stem cells

Authors: Tan Boon Toh, Jhin Jieh Lim, Edward Kai-Hua Chow

Published in: Molecular Cancer | Issue 1/2017

Login to get access

Abstract

Compelling evidence have demonstrated that bulk tumors can arise from a unique subset of cells commonly termed “cancer stem cells” that has been proposed to be a strong driving force of tumorigenesis and a key mechanism of therapeutic resistance. Recent advances in epigenomics have illuminated key mechanisms by which epigenetic regulation contribute to cancer progression. In this review, we present a discussion of how deregulation of various epigenetic pathways can contribute to cancer initiation and tumorigenesis, particularly with respect to maintenance and survival of cancer stem cells. This information, together with several promising clinical and preclinical trials of epigenetic modulating drugs, offer new possibilities for targeting cancer stem cells as well as improving cancer therapy overall.
Literature
1.
Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.PubMedCrossRef
2.
Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–7.PubMedCrossRef
3.
Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645–8.PubMedCrossRef
4.
Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445:111–5.PubMedCrossRef
5.
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB. Identification of human brain tumour initiating cells. Nature. 2004;432:396–401.PubMedCrossRef
6.
Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, Jordan S, Duncan LM, Weishaupt C, et al. Identification of cells initiating human melanomas. Nature. 2008;451:345–9.PubMedPubMedCentralCrossRef
7.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100:3983–8.PubMedPubMedCentralCrossRef
8.
Zhang S, Balch C, Chan MW, Lai HC, Matei D, Schilder JM, Yan PS, Huang TH, Nephew KP. Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res. 2008;68:4311–20.PubMedPubMedCentralCrossRef
9.
Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO, Zheng BJ, Guan XY. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology. 2007;132:2542–56.PubMedCrossRef
10.
Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65:10946–51.PubMedCrossRef
11.
Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, Conticello C, Ruco L, Peschle C, De Maria R. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 2008;15:504–14.PubMedCrossRef
12.
Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, Aigner L, Brawanski A, Bogdahn U, Beier CP. CD133(+) and CD133(−) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res. 2007;67:4010–5.PubMedCrossRef
13.
Kemper K, Sprick MR, de Bree M, Scopelliti A, Vermeulen L, Hoek M, Zeilstra J, Pals ST, Mehmet H, Stassi G, Medema JP. The AC133 epitope, but not the CD133 protein, is lost upon cancer stem cell differentiation. Cancer Res. 2010;70:719–29.PubMedCrossRef
14.
Zhou F, Cui C, Ge Y, Chen H, Li Q, Yang Z, Wu G, Sun S, Chen K, Gu J, et al. Alpha2,3-Sialylation regulates the stability of stem cell marker CD133. J Biochem. 2010;148:273–80.PubMedCrossRef
15.
Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, Jia H, Ye Q, Qin LX, Wauthier E, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009;136:1012–24.PubMedCrossRef
16.
Wilson GS, Hu Z, Duan W, Tian A, Wang XM, McLeod D, Lam V, George J, Qiao L. Efficacy of using cancer stem cell markers in isolating and characterizing liver cancer stem cells. Stem Cells Dev. 2013;22:2655–64.PubMedPubMedCentralCrossRef
17.
18.
Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ. Efficient tumour formation by single human melanoma cells. Nature. 2008;456:593–8.PubMedPubMedCentralCrossRef
19.
Bar EE, Chaudhry A, Lin A, Fan X, Schreck K, Matsui W, Piccirillo S, Vescovi AL, DiMeco F, Olivi A, Eberhart CG. Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells. 2007;25:2524–33.PubMedPubMedCentralCrossRef
20.
Sakariassen PO, Prestegarden L, Wang J, Skaftnesmo KO, Mahesparan R, Molthoff C, Sminia P, Sundlisaeter E, Misra A, Tysnes BB, et al. Angiogenesis-independent tumor growth mediated by stem-like cancer cells. Proc Natl Acad Sci U S A. 2006;103:16466–71.PubMedPubMedCentralCrossRef
21.
Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, Asselin-Labat ML, Gyorki DE, Ward T, Partanen A, et al. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med. 2009;15:907–13.PubMedCrossRef
22.
Molyneux G, Geyer FC, Magnay FA, McCarthy A, Kendrick H, Natrajan R, Mackay A, Grigoriadis A, Tutt A, Ashworth A, et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell. 2010;7:403–17.PubMedCrossRef
23.
Eppert K, Takenaka K, Lechman ER, Waldron L, Nilsson B, van Galen P, Metzeler KH, Poeppl A, Ling V, Beyene J, et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med. 2011;17:1086–93.PubMedCrossRef
24.
Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ, Lerner J, Brunet JP, Subramanian A, Ross KN, et al. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science. 2006;313:1929–35.PubMedCrossRef
25.
Shats I, Gatza ML, Chang JT, Mori S, Wang J, Rich J, Nevins JR. Using a stem cell-based signature to guide therapeutic selection in cancer. Cancer Res. 2011;71:1772–80.PubMedCrossRef
26.
Reik W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature. 2007;447:425–32.PubMedCrossRef
27.
Stallcup MR. Role of protein methylation in chromatin remodeling and transcriptional regulation. Oncogene. 2001;20:3014–20.PubMedCrossRef
28.
29.
Wongtrakoongate P. Epigenetic therapy of cancer stem and progenitor cells by targeting DNA methylation machineries. World J Stem Cells. 2015;7:137–48.PubMedPubMedCentralCrossRef
30.
Esteller M. Epigenetic gene silencing in cancer: the DNA hypermethylome. Hum Mol Genet. 2007;16 Spec No 1:R50–59.PubMedCrossRef
31.
Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE, Cope L, Mohammad HP, Chen W, Daniel VC, Yu W, et al. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet. 2007;39:237–42.PubMedPubMedCentralCrossRef
32.
33.
Broske AM, Vockentanz L, Kharazi S, Huska MR, Mancini E, Scheller M, Kuhl C, Enns A, Prinz M, Jaenisch R, et al. DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat Genet. 2009;41:1207–15.PubMedCrossRef
34.
Liu CC, Lin JH, Hsu TW, Su K, Li AF, Hsu HS, Hung SC. IL-6 enriched lung cancer stem-like cell population by inhibition of cell cycle regulators via DNMT1 upregulation. Int J Cancer. 2015;136:547–59.PubMed
35.
Morita R, Hirohashi Y, Suzuki H, Takahashi A, Tamura Y, Kanaseki T, Asanuma H, Inoda S, Kondo T, Hashino S, et al. DNA methyltransferase 1 is essential for initiation of the colon cancers. Exp Mol Pathol. 2013;94:322–9.PubMedCrossRef
36.
Hoffmeyer K, Raggioli A, Rudloff S, Anton R, Hierholzer A, Del Valle I, Hein K, Vogt R, Kemler R. Wnt/beta-catenin signaling regulates telomerase in stem cells and cancer cells. Science. 2012;336:1549–54.PubMedCrossRef
37.
Myant KB, Cammareri P, McGhee EJ, Ridgway RA, Huels DJ, Cordero JB, Schwitalla S, Kalna G, Ogg EL, Athineos D, et al. ROS production and NF-kappaB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell Stem Cell. 2013;12:761–73.PubMedPubMedCentralCrossRef
38.
Barker N, Clevers H. Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov. 2006;5:997–1014.PubMedCrossRef
39.
40.
Lindvall C, Bu W, Williams BO, Li Y. Wnt signaling, stem cells, and the cellular origin of breast cancer. Stem Cell Rev. 2007;3:157–68.PubMedCrossRef
41.
Klarmann GJ, Decker A, Farrar WL. Epigenetic gene silencing in the Wnt pathway in breast cancer. Epigenetics. 2008;3:59–63.PubMedCrossRef
42.
Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Chen WD, Pretlow TP, Yang B, Akiyama Y, Van Engeland M, et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet. 2004;36:417–22.PubMedCrossRef
43.
Koinuma K, Yamashita Y, Liu W, Hatanaka H, Kurashina K, Wada T, Takada S, Kaneda R, Choi YL, Fujiwara SI, et al. Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability. Oncogene. 2006;25:139–46.PubMed
44.
Yoda Y, Takeshima H, Niwa T, Kim JG, Ando T, Kushima R, Sugiyama T, Katai H, Noshiro H, Ushijima T. Integrated analysis of cancer-related pathways affected by genetic and epigenetic alterations in gastric cancer. Gastric Cancer. 2015;18:65–76.PubMedCrossRef
45.
Hussain M, Rao M, Humphries AE, Hong JA, Liu F, Yang M, Caragacianu D, Schrump DS. Tobacco smoke induces polycomb-mediated repression of Dickkopf-1 in lung cancer cells. Cancer Res. 2009;69:3570–8.PubMedCrossRef
46.
Jiang X, Tan J, Li J, Kivimae S, Yang X, Zhuang L, Lee PL, Chan MT, Stanton LW, Liu ET, et al. DACT3 is an epigenetic regulator of Wnt/beta-catenin signaling in colorectal cancer and is a therapeutic target of histone modifications. Cancer Cell. 2008;13:529–41.PubMedPubMedCentralCrossRef
47.
Rheinbay E, Suva ML, Gillespie SM, Wakimoto H, Patel AP, Shahid M, Oksuz O, Rabkin SD, Martuza RL, Rivera MN, et al. An aberrant transcription factor network essential for Wnt signaling and stem cell maintenance in glioblastoma. Cell Rep. 2013;3:1567–79.PubMedPubMedCentralCrossRef
48.
Zhang N, Wei P, Gong A, Chiu WT, Lee HT, Colman H, Huang H, Xue J, Liu M, Wang Y, et al. FoxM1 promotes beta-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis. Cancer Cell. 2011;20:427–42.PubMedPubMedCentralCrossRef
49.
Zheng H, Ying H, Wiedemeyer R, Yan H, Quayle SN, Ivanova EV, Paik JH, Zhang H, Xiao Y, Perry SR, et al. PLAGL2 regulates Wnt signaling to impede differentiation in neural stem cells and gliomas. Cancer Cell. 2010;17:497–509.PubMedPubMedCentralCrossRef
50.
Wang Y, He L, Du Y, Zhu P, Huang G, Luo J, Yan X, Ye B, Li C, Xia P, et al. The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling. Cell Stem Cell. 2015;16:413–25.PubMedCrossRef
51.
Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001;15:3059–87.PubMedCrossRef
52.
Ma J, Meng Y, Kwiatkowski DJ, Chen X, Peng H, Sun Q, Zha X, Wang F, Wang Y, Jing Y, et al. Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade. J Clin Invest. 2010;120:103–14.PubMedCrossRef
53.
Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature. 2004;432:324–31.PubMedCrossRef
54.
Teglund S, Toftgard R. Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim Biophys Acta. 1805;2010:181–208.
55.
Youssef KK, Van Keymeulen A, Lapouge G, Beck B, Michaux C, Achouri Y, Sotiropoulou PA, Blanpain C. Identification of the cell lineage at the origin of basal cell carcinoma. Nat Cell Biol. 2010;12:299–305.PubMed
56.
Sellheyer K. Basal cell carcinoma: cell of origin, cancer stem cell hypothesis and stem cell markers. Br J Dermatol. 2011;164:696–711.PubMedCrossRef
57.
Yang ZJ, Ellis T, Markant SL, Read TA, Kessler JD, Bourboulas M, Schuller U, Machold R, Fishell G, Rowitch DH, et al. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell. 2008;14:135–45.PubMedPubMedCentralCrossRef
58.
Schuller U, Heine VM, Mao J, Kho AT, Dillon AK, Han YG, Huillard E, Sun T, Ligon AH, Qian Y, et al. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell. 2008;14:123–34.PubMedPubMedCentralCrossRef
59.
Biegel JA, Zhou JY, Rorke LB, Stenstrom C, Wainwright LM, Fogelgren B. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 1999;59:74–9.PubMed
60.
Sevenet N, Sheridan E, Amram D, Schneider P, Handgretinger R, Delattre O. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet. 1999;65:1342–8.PubMedPubMedCentralCrossRef
61.
Versteege I, Sevenet N, Lange J, Rousseau-Merck MF, Ambros P, Handgretinger R, Aurias A, Delattre O. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature. 1998;394:203–6.PubMedCrossRef
62.
Canettieri G, Di Marcotullio L, Greco A, Coni S, Antonucci L, Infante P, Pietrosanti L, De Smaele E, Ferretti E, Miele E, et al. Histone deacetylase and Cullin3-REN(KCTD11) ubiquitin ligase interplay regulates Hedgehog signalling through Gli acetylation. Nat Cell Biol. 2010;12:132–42.PubMedCrossRef
63.
Di Marcotullio L, Ferretti E, De Smaele E, Argenti B, Mincione C, Zazzeroni F, Gallo R, Masuelli L, Napolitano M, Maroder M, et al. REN(KCTD11) is a suppressor of Hedgehog signaling and is deleted in human medulloblastoma. Proc Natl Acad Sci U S A. 2004;101:10833–8.PubMedPubMedCentralCrossRef
64.
Cui W, Wang LH, Wen YY, Song M, Li BL, Chen XL, Xu M, An SX, Zhao J, Lu YY, et al. Expression and regulation mechanisms of Sonic Hedgehog in breast cancer. Cancer Sci. 2010;101:927–33.PubMedCrossRef
65.
Wang LH, Choi YL, Hua XY, Shin YK, Song YJ, Youn SJ, Yun HY, Park SM, Kim WJ, Kim HJ, et al. Increased expression of sonic hedgehog and altered methylation of its promoter region in gastric cancer and its related lesions. Mod Pathol. 2006;19:675–83.PubMedCrossRef
66.
Duan ZH, Wang HC, Zhao DM, Ji XX, Song M, Yang XJ, Cui W. Cooperatively transcriptional and epigenetic regulation of sonic hedgehog overexpression drives malignant potential of breast cancer. Cancer Sci. 2015;106:1084–91.PubMedPubMedCentralCrossRef
67.
Andersson ER, Lendahl U. Therapeutic modulation of Notch signalling--are we there yet? Nat Rev Drug Discov. 2014;13:357–78.PubMedCrossRef
68.
Kopan R. Notch signaling. Cold Spring Harb Perspect Biol. 2012;4.
69.
Andersson ER, Sandberg R, Lendahl U. Notch signaling: simplicity in design, versatility in function. Development. 2011;138:3593–612.PubMedCrossRef
70.
Munoz P, Iliou MS, Esteller M. Epigenetic alterations involved in cancer stem cell reprogramming. Mol Oncol. 2012;6:620–36.PubMedCrossRef
71.
Liu J, Sato C, Cerletti M, Wagers A. Notch signaling in the regulation of stem cell self-renewal and differentiation. Curr Top Dev Biol. 2010;92:367–409.PubMedCrossRef
72.
Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, Rueger MA, Bae SK, Kittappa R, McKay RD. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature. 2006;442:823–6.PubMedCrossRef
73.
Lopez-Arribillaga E, Rodilla V, Pellegrinet L, Guiu J, Iglesias M, Roman AC, Gutarra S, Gonzalez S, Munoz-Canoves P, Fernandez-Salguero P, et al. Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch. Development. 2015;142:41–50.PubMedCrossRef
74.
Yuan X, Wu H, Han N, Xu H, Chu Q, Yu S, Chen Y, Wu K. Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application. J Hematol Oncol. 2014;7:87.PubMedPubMedCentralCrossRef
75.
Ichida JK, Tcw J, Williams LA, Carter AC, Shi Y, Moura MT, Ziller M, Singh S, Amabile G, Bock C, et al. Notch inhibition allows oncogene-independent generation of iPS cells. Nat Chem Biol. 2014;10:632–9.PubMedPubMedCentralCrossRef
76.
Zou J, Li P, Lu F, Liu N, Dai J, Ye J, Qu X, Sun X, Ma D, Park J, Ji C. Notch1 is required for hypoxia-induced proliferation, invasion and chemoresistance of T-cell acute lymphoblastic leukemia cells. J Hematol Oncol. 2013;6:3.PubMedPubMedCentralCrossRef
77.
Gallahan D, Callahan R. The mouse mammary tumor associated gene INT3 is a unique member of the NOTCH gene family (NOTCH4). Oncogene. 1997;14:1883–90.PubMedCrossRef
78.
D’Angelo RC, Ouzounova M, Davis A, Choi D, Tchuenkam SM, Kim G, Luther T, Quraishi AA, Senbabaoglu Y, Conley SJ, et al. Notch reporter activity in breast cancer cell lines identifies a subset of cells with stem cell activity. Mol Cancer Ther. 2015;14:779–87.PubMedPubMedCentralCrossRef
79.
Wang Z, Da Silva TG, Jin K, Han X, Ranganathan P, Zhu X, Sanchez-Mejias A, Bai F, Li B, Fei DL, et al. Notch signaling drives stemness and tumorigenicity of esophageal adenocarcinoma. Cancer Res. 2014;74:6364–74.PubMedPubMedCentralCrossRef
80.
Jin L, Vu TT, Datta PK. Abstract 1709: STRAP mediates the stemness of human colorectal cancer cells by epigenetic regulation of Notch pathway. Cancer Res. 2016;76:1709.CrossRef
81.
Ghoshal P, Nganga AJ, Moran-Giuati J, Szafranek A, Johnson TR, Bigelow AJ, Houde CM, Avet-Loiseau H, Smiraglia DJ, Ersing N, et al. Loss of the SMRT/NCoR2 corepressor correlates with JAG2 overexpression in multiple myeloma. Cancer Res. 2009;69:4380–7.PubMedCrossRef
82.
83.
Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.PubMedCrossRef
84.
Morel A-P, Lièvre M, Thomas C, Hinkal G, Ansieau S, Puisieux A. Generation of Breast Cancer Stem Cells through Epithelial-Mesenchymal Transition. PLoS One. 2008;3:e2888.PubMedPubMedCentralCrossRef
85.
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.PubMedPubMedCentralCrossRef
86.
Dissanayake SK, Wade M, Johnson CE, O’Connell MP, Leotlela PD, French AD, Shah KV, Hewitt KJ, Rosenthal DT, Indig FE, et al. The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition. J Biol Chem. 2007;282:17259–71.PubMedPubMedCentralCrossRef
87.
Vincan E, Barker N. The upstream components of the Wnt signalling pathway in the dynamic EMT and MET associated with colorectal cancer progression. Clin Exp Metastasis. 2008;25:657–63.PubMedCrossRef
88.
89.
Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008;14:818–29.PubMedCrossRef
90.
Dohadwala M, Yang SC, Luo J, Sharma S, Batra RK, Huang M, Lin Y, Goodglick L, Krysan K, Fishbein MC, et al. Cyclooxygenase-2-dependent regulation of E-cadherin: prostaglandin E(2) induces transcriptional repressors ZEB1 and snail in non-small cell lung cancer. Cancer Res. 2006;66:5338–45.PubMedCrossRef
91.
Dumont N, Wilson MB, Crawford YG, Reynolds PA, Sigaroudinia M, Tlsty TD. Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers. Proc Natl Acad Sci U S A. 2008;105:14867–72.PubMedPubMedCentralCrossRef
92.
Gibbons DL, Lin W, Creighton CJ, Rizvi ZH, Gregory PA, Goodall GJ, Thilaganathan N, Du L, Zhang Y, Pertsemlidis A, Kurie JM. Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression. Genes Dev. 2009;23:2140–51.PubMedPubMedCentralCrossRef
93.
Avgustinova A, Benitah SA. The epigenetics of tumour initiation: cancer stem cells and their chromatin. Curr Opin Genet Dev. 2016;36:8–15.PubMedCrossRef
94.
Koizume S, Tachibana K, Sekiya T, Hirohashi S, Shiraishi M. Heterogeneity in the modification and involvement of chromatin components of the CpG island of the silenced human CDH1 gene in cancer cells. Nucleic Acids Res. 2002;30:4770–80.PubMedPubMedCentralCrossRef
95.
Wang Y, Shang Y. Epigenetic control of epithelial-to-mesenchymal transition and cancer metastasis. Exp Cell Res. 2013;319:160–9.PubMedCrossRef
96.
Cao Q, Yu J, Dhanasekaran SM, Kim JH, Mani RS, Tomlins SA, Mehra R, Laxman B, Cao X, Yu J, et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene. 2008;27:7274–84.PubMedPubMedCentralCrossRef
97.
Herranz N, Pasini D, Diaz VM, Franci C, Gutierrez A, Dave N, Escriva M, Hernandez-Munoz I, Di Croce L, Helin K, et al. Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor. Mol Cell Biol. 2008;28:4772–81.PubMedPubMedCentralCrossRef
98.
Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10:593–601.PubMedCrossRef
99.
Korpal M, Lee ES, Hu G, Kang Y. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem. 2008;283:14910–4.PubMedPubMedCentralCrossRef
100.
Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 2008;22:894–907.PubMedPubMedCentralCrossRef
101.
Chang CJ, Chao CH, Xia W, Yang JY, Xiong Y, Li CW, Yu WH, Rehman SK, Hsu JL, Lee HH, et al. p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol. 2011;13:317–23.PubMedPubMedCentralCrossRef
102.
Tellez CS, Juri DE, Do K, Bernauer AM, Thomas CL, Damiani LA, Tessema M, Leng S, Belinsky SA. EMT and stem cell-like properties associated with miR-205 and miR-200 epigenetic silencing are early manifestations during carcinogen-induced transformation of human lung epithelial cells. Cancer Res. 2011;71:3087–97.PubMedPubMedCentralCrossRef
103.
Shah AN, Summy JM, Zhang J, Park SI, Parikh NU, Gallick GE. Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann Surg Oncol. 2007;14:3629–37.PubMedCrossRef
104.
Wang Z, Li Y, Kong D, Banerjee S, Ahmad A, Azmi AS, Ali S, Abbruzzese JL, Gallick GE, Sarkar FH. Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res. 2009;69:2400–7.PubMedPubMedCentralCrossRef
105.
Shukla S, Meeran SM. Epigenetics of cancer stem cells: Pathways and therapeutics. Biochim Biophys Acta. 1840;2014:3494–502.
106.
Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL, Gallick GE, Logsdon CD, McConkey DJ, Choi W. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009;69:5820–8.PubMedPubMedCentralCrossRef
107.
Wu CP, Calcagno AM, Ambudkar SV. Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells: evaluation of current strategies. Curr Mol Pharmacol. 2008;1:93–105.PubMedPubMedCentralCrossRef
108.
Wang X, Low XC, Hou W, Abdullah LN, Toh TB. Mohd Abdul Rashid M, Ho D, Chow EK: Epirubicin-adsorbed nanodiamonds kill chemoresistant hepatic cancer stem cells. ACS Nano. 2014;8:12151–66.PubMedPubMedCentralCrossRef
109.
Cho S, Lu M, He X, Ee PL, Bhat U, Schneider E, Miele L, Beck WT. Notch1 regulates the expression of the multidrug resistance gene ABCC1/MRP1 in cultured cancer cells. Proc Natl Acad Sci U S A. 2011;108:20778–83.PubMedPubMedCentralCrossRef
110.
Kim B, Stephen SL, Hanby AM, Horgan K, Perry SL, Richardson J, Roundhill EA, Valleley EM, Verghese ET, Williams BJ, et al. Chemotherapy induces Notch1-dependent MRP1 up-regulation, inhibition of which sensitizes breast cancer cells to chemotherapy. BMC Cancer. 2015;15:634.PubMedPubMedCentralCrossRef
111.
To KK, Polgar O, Huff LM, Morisaki K, Bates SE. Histone modifications at the ABCG2 promoter following treatment with histone deacetylase inhibitor mirror those in multidrug-resistant cells. Mol Cancer Res. 2008;6:151–64.PubMedPubMedCentralCrossRef
112.
113.
Stresemann C, Lyko F. Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008;123:8–13.PubMedCrossRef
114.
Juttermann R, Li E, Jaenisch R. Toxicity of 5-aza-2′-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation. Proc Natl Acad Sci U S A. 1994;91:11797–801.PubMedPubMedCentralCrossRef
115.
Ghoshal K, Datta J, Majumder S, Bai S, Kutay H, Motiwala T, Jacob ST. 5-Aza-deoxycytidine induces selective degradation of DNA methyltransferase 1 by a proteasomal pathway that requires the KEN box, bromo-adjacent homology domain, and nuclear localization signal. Mol Cell Biol. 2005;25:4727–41.PubMedPubMedCentralCrossRef
116.
Sorm F, Vesely J. the activity of a new antimetabolite, 5-azacytidine, against lymphoid leukaemia in ak mice. Neoplasma. 1964;11:123–30.PubMed
117.
Abele R, Clavel M, Dodion P, Bruntsch U, Gundersen S, Smyth J, Renard J, van Glabbeke M, Pinedo HM. The EORTC Early Clinical Trials Cooperative Group experience with 5-aza-2′-deoxycytidine (NSC 127716) in patients with colo-rectal, head and neck, renal carcinomas and malignant melanomas. Eur J Cancer Clin Oncol. 1987;23:1921–4.PubMedCrossRef
118.
Cowan LA, Talwar S, Yang AS. Will DNA methylation inhibitors work in solid tumors? A review of the clinical experience with azacitidine and decitabine in solid tumors. Epigenomics. 2010;2:71–86.PubMedCrossRef
119.
Clavel M, Monfardini S, Fossa S, Smyth J, Renard J, Kaye SB. 5-Aza-2′-deoxycytidine (NSC 127716) in non-seminomatous testicular cancer. Phase II from the EORTC Early Clinical Trials Cooperative Group and Genito-Urinary Group. Ann Oncol. 1992;3:399–400.PubMedCrossRef
120.
Stadler WM, Margolin K, Ferber S, McCulloch W, Thompson JA. A phase II study of depsipeptide in refractory metastatic renal cell cancer. Clin Genitourin Cancer. 2006;5:57–60.PubMedCrossRef
121.
Tsai HC, Li H, Van Neste L, Cai Y, Robert C, Rassool FV, Shin JJ, Harbom KM, Beaty R, Pappou E, et al. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell. 2012;21:430–46.PubMedPubMedCentralCrossRef
122.
Pinto A, Zagonel V, Attadia V, Bullian PL, Gattei V, Carbone A, Monfardini S, Colombatti A. 5-Aza-2′-deoxycytidine as a differentiation inducer in acute myeloid leukaemias and myelodysplastic syndromes of the elderly. Bone Marrow Transplant. 1989;4 Suppl 3:28–32.PubMed
123.
Zagonel V, Lo Re G, Marotta G, Babare R, Sardeo G, Gattei V, De Angelis V, Monfardini S, Pinto A. 5-Aza-2′-deoxycytidine (Decitabine) induces trilineage response in unfavourable myelodysplastic syndromes. Leukemia. 1993;7 Suppl 1:30–5.PubMed
124.
Tian J, Lee SO, Liang L, Luo J, Huang CK, Li L, Niu Y, Chang C. Targeting the unique methylation pattern of androgen receptor (AR) promoter in prostate stem/progenitor cells with 5-aza-2′-deoxycytidine (5-AZA) leads to suppressed prostate tumorigenesis. J Biol Chem. 2012;287:39954–66.PubMedPubMedCentralCrossRef
125.
Wang Y, Cardenas H, Fang F, Condello S, Taverna P, Segar M, Liu Y, Nephew KP, Matei D. Epigenetic targeting of ovarian cancer stem cells. Cancer Res. 2014;74:4922–36.PubMedPubMedCentralCrossRef
126.
Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R. FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist. 2005;10:176–82.PubMedCrossRef
127.
Finley A, Copeland RA. Small molecule control of chromatin remodeling. Chem Biol. 2014;21:1196–210.PubMedCrossRef
128.
de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2003;370:737–49.PubMedPubMedCentralCrossRef
129.
Johnstone RW, Licht JD. Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? Cancer Cell. 2003;4:13–8.PubMedCrossRef
130.
Gelmetti V, Zhang J, Fanelli M, Minucci S, Pelicci PG, Lazar MA. Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Mol Cell Biol. 1998;18:7185–91.PubMedPubMedCentralCrossRef
131.
Luo J, Su F, Chen D, Shiloh A, Gu W. Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature. 2000;408:377–81.PubMedCrossRef
132.
Duan H, Heckman CA, Boxer LM. Histone deacetylase inhibitors down-regulate bcl-2 expression and induce apoptosis in t(14;18) lymphomas. Mol Cell Biol. 2005;25:1608–19.PubMedPubMedCentralCrossRef
133.
Federico M, Bagella L. Histone deacetylase inhibitors in the treatment of hematological malignancies and solid tumors. J Biomed Biotechnol. 2011;2011:475641.PubMedCrossRef
134.
Juo YY, Gong XJ, Mishra A, Cui X, Baylin SB, Azad NS, Ahuja N. Epigenetic therapy for solid tumors: from bench science to clinical trials. Epigenomics. 2015;7:215–35.PubMedCrossRef
135.
Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, Frankel SR, Chen C, Ricker JL, Arduino JM, Duvic M. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007;25:3109–15.PubMedCrossRef
136.
Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH, Zain J, Prince HM, Leonard JP, Geskin LJ, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009;27:5410–7.PubMedPubMedCentralCrossRef
137.
Thaler F. Current trends in the development of histone deacetylase inhibitors: a review of recent patent applications. Pharm Pat Anal. 2012;1:75–90.PubMedCrossRef
138.
Whittaker SJ, Demierre MF, Kim EJ, Rook AH, Lerner A, Duvic M, Scarisbrick J, Reddy S, Robak T, Becker JC, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol. 2010;28:4485–91.PubMedCrossRef
139.
Vansteenkiste J, Van Cutsem E, Dumez H, Chen C, Ricker JL, Randolph SS, Schoffski P. Early phase II trial of oral vorinostat in relapsed or refractory breast, colorectal, or non-small cell lung cancer. Invest New Drugs. 2008;26:483–8.PubMedCrossRef
140.
Luu TH, Morgan RJ, Leong L, Lim D, McNamara M, Portnow J, Frankel P, Smith DD, Doroshow JH, Wong C, et al. A phase II trial of vorinostat (suberoylanilide hydroxamic acid) in metastatic breast cancer: a California Cancer Consortium study. Clin Cancer Res. 2008;14:7138–42.PubMedPubMedCentralCrossRef
141.
Woyach JA, Kloos RT, Ringel MD, Arbogast D, Collamore M, Zwiebel JA, Grever M, Villalona-Calero M, Shah MH. Lack of therapeutic effect of the histone deacetylase inhibitor vorinostat in patients with metastatic radioiodine-refractory thyroid carcinoma. J Clin Endocrinol Metab. 2009;94:164–70.PubMedCrossRef
142.
Modesitt SC, Sill M, Hoffman JS, Bender DP. A phase II study of vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2008;109:182–6.PubMedCrossRef
143.
Blumenschein Jr GR, Kies MS, Papadimitrakopoulou VA, Lu C, Kumar AJ, Ricker JL, Chiao JH, Chen C, Frankel SR. Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinza, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Invest New Drugs. 2008;26:81–7.PubMedCrossRef
144.
Traynor AM, Dubey S, Eickhoff JC, Kolesar JM, Schell K, Huie MS, Groteluschen DL, Marcotte SM, Hallahan CM, Weeks HR, et al. Vorinostat (NSC# 701852) in patients with relapsed non-small cell lung cancer: a Wisconsin Oncology Network phase II study. J Thorac Oncol. 2009;4:522–6.PubMedPubMedCentralCrossRef
145.
Galanis E, Jaeckle KA, Maurer MJ, Reid JM, Ames MM, Hardwick JS, Reilly JF, Loboda A, Nebozhyn M, Fantin VR, et al. Phase II trial of vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study. J Clin Oncol. 2009;27:2052–8.PubMedPubMedCentralCrossRef
146.
Schrump DS, Fischette MR, Nguyen DM, Zhao M, Li X, Kunst TF, Hancox A, Hong JA, Chen GA, Kruchin E, et al. Clinical and molecular responses in lung cancer patients receiving Romidepsin. Clin Cancer Res. 2008;14:188–98.PubMedCrossRef
147.
Otterson GA, Hodgson L, Pang H, Vokes EE. Cancer, Leukemia Group B: Phase II study of the histone deacetylase inhibitor Romidepsin in relapsed small cell lung cancer (Cancer and Leukemia Group B 30304). J Thorac Oncol. 2010;5:1644–8.PubMedPubMedCentralCrossRef
148.
Iwamoto FM, Lamborn KR, Kuhn JG, Wen PY, Yung WK, Gilbert MR, Chang SM, Lieberman FS, Prados MD, Fine HA. A phase I/II trial of the histone deacetylase inhibitor romidepsin for adults with recurrent malignant glioma: North American Brain Tumor Consortium Study 03–03. Neuro Oncol. 2011;13:509–16.PubMedPubMedCentralCrossRef
149.
Whitehead RP, Rankin C, Hoff PM, Gold PJ, Billingsley KG, Chapman RA, Wong L, Ward JH, Abbruzzese JL, Blanke CD. Phase II trial of romidepsin (NSC-630176) in previously treated colorectal cancer patients with advanced disease: a Southwest Oncology Group study (S0336). Invest New Drugs. 2009;27:469–75.PubMedCrossRef
150.
Molife LR, Attard G, Fong PC, Karavasilis V, Reid AH, Patterson S, Riggs Jr CE, Higano C, Stadler WM, McCulloch W, et al. Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC). Ann Oncol. 2010;21:109–13.PubMedCrossRef
151.
152.
153.
Lane AA, Chabner BA. Histone deacetylase inhibitors in cancer therapy. J Clin Oncol. 2009;27:5459–68.PubMedCrossRef
154.
Tarhini AA, Zahoor H, McLaughlin B, Gooding WE, Schmitz JC, Siegfried JM, Socinski MA, Argiris A. Phase I trial of carboplatin and etoposide in combination with panobinostat in patients with lung cancer. Anticancer Res. 2013;33:4475–81.PubMedPubMedCentral
155.
Cassier PA, Lefranc A, Amela EY, Chevreau C, Bui BN, Lecesne A, Ray-Coquard I, Chabaud S, Penel N, Berge Y, et al. A phase II trial of panobinostat in patients with advanced pretreated soft tissue sarcoma. A study from the French Sarcoma Group. Br J Cancer. 2013;109:909–14.PubMedPubMedCentralCrossRef
156.
Witta SE, Jotte RM, Konduri K, Neubauer MA, Spira AI, Ruxer RL, Varella-Garcia M, Bunn Jr PA, Hirsch FR. Randomized phase II trial of erlotinib with and without entinostat in patients with advanced non-small-cell lung cancer who progressed on prior chemotherapy. J Clin Oncol. 2012;30:2248–55.PubMedPubMedCentralCrossRef
157.
Yardley DA, Ismail-Khan RR, Melichar B, Lichinitser M, Munster PN, Klein PM, Cruickshank S, Miller KD, Lee MJ, Trepel JB. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J Clin Oncol. 2013;31:2128–35.PubMedPubMedCentralCrossRef
158.
Yeo W, Chung HC, Chan SL, Wang LZ, Lim R, Picus J, Boyer M, Mo FK, Koh J, Rha SY, et al. Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the mayo phase II consortium and the cancer therapeutics research group. J Clin Oncol. 2012;30:3361–7.PubMedPubMedCentralCrossRef
159.
Dizon DS, Blessing JA, Penson RT, Drake RD, Walker JL, Johnston CM, Disilvestro PA, Fader AN. a phase ii evaluation of belinostat and carboplatin in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal carcinoma: a gynecologic oncology group study. Gynecol Oncol. 2012;125:367–71.PubMedPubMedCentralCrossRef
160.
Zorzi AP, Bernstein M, Samson Y, Wall DA, Desai S, Nicksy D, Wainman N, Eisenhauer E, Baruchel S. A phase I study of histone deacetylase inhibitor, pracinostat (SB939), in pediatric patients with refractory solid tumors: IND203 a trial of the NCIC IND program/C17 pediatric phase I consortium. Pediatr Blood Cancer. 2013;60:1868–74.PubMedCrossRef
161.
Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S, McDermott U, Azizian N, Zou L, Fischbach MA, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010;141:69–80.PubMedPubMedCentralCrossRef
162.
Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F, Nervi C, Pelicci PG, Heinzel T. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. Embo j. 2001;20:6969–78.PubMedPubMedCentralCrossRef
163.
Travaglini L, Vian L, Billi M, Grignani F, Nervi C. Epigenetic reprogramming of breast cancer cells by valproic acid occurs regardless of estrogen receptor status. Int J Biochem Cell Biol. 2009;41:225–34.PubMedCrossRef
164.
Schech A, Kazi A, Yu S, Shah P, Sabnis G. Histone Deacetylase Inhibitor Entinostat Inhibits Tumor-Initiating Cells in Triple-Negative Breast Cancer Cells. Mol Cancer Ther. 2015;14:1848–57.PubMedCrossRef
165.
Song Y, Wu F, Wu J. Targeting histone methylation for cancer therapy: enzymes, inhibitors, biological activity and perspectives. J Hematol Oncol. 2016;9:49.PubMedPubMedCentralCrossRef
166.
167.
Copeland RA, Solomon ME, Richon VM. Protein methyltransferases as a target class for drug discovery. Nat Rev Drug Discov. 2009;8:724–32.PubMedCrossRef
168.
Bhaumik SR, Smith E, Shilatifard A. Covalent modifications of histones during development and disease pathogenesis. Nat Struct Mol Biol. 2007;14:1008–16.PubMedCrossRef
169.
Basavapathruni A, Jin L, Daigle SR, Majer CR, Therkelsen CA, Wigle TJ, Kuntz KW, Chesworth R, Pollock RM, Scott MP, et al. Conformational adaptation drives potent, selective and durable inhibition of the human protein methyltransferase DOT1L. Chem Biol Drug Des. 2012;80:971–80.PubMedCrossRef
170.
Liu Y, Liu K, Qin S, Xu C, Min J. Epigenetic targets and drug discovery: part 1: histone methylation. Pharmacol Ther. 2014;143:275–94.PubMedCrossRef
171.
Liu K, Liu Y, Lau JL, Min J. Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation. Pharmacol Ther. 2015;151:121–40.PubMedCrossRef
172.
McGrath J, Trojer P. Targeting histone lysine methylation in cancer. Pharmacol Ther. 2015;150:1–22.PubMedCrossRef
173.
Copeland RA, Moyer MP, Richon VM. Targeting genetic alterations in protein methyltransferases for personalized cancer therapeutics. Oncogene. 2013;32:939–46.PubMedCrossRef
174.
Steger DJ, Lefterova MI, Ying L, Stonestrom AJ, Schupp M, Zhuo D, Vakoc AL, Kim JE, Chen J, Lazar MA, et al. DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells. Mol Cell Biol. 2008;28:2825–39.PubMedPubMedCentralCrossRef
175.
Wang Z, Zang C, Rosenfeld JA, Schones DE, Barski A, Cuddapah S, Cui K, Roh TY, Peng W, Zhang MQ, Zhao K. Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genet. 2008;40:897–903.PubMedPubMedCentralCrossRef
176.
Mueller D, Bach C, Zeisig D, Garcia-Cuellar MP, Monroe S, Sreekumar A, Zhou R, Nesvizhskii A, Chinnaiyan A, Hess JL, Slany RK. A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood. 2007;110:4445–54.PubMedPubMedCentralCrossRef
177.
Bitoun E, Oliver PL, Davies KE. The mixed-lineage leukemia fusion partner AF4 stimulates RNA polymerase II transcriptional elongation and mediates coordinated chromatin remodeling. Hum Mol Genet. 2007;16:92–106.PubMedCrossRef
178.
Zhang W, Xia X, Reisenauer MR, Hemenway CS, Kone BC. Dot1a-AF9 complex mediates histone H3 Lys-79 hypermethylation and repression of ENaCalpha in an aldosterone-sensitive manner. J Biol Chem. 2006;281:18059–68.PubMedPubMedCentralCrossRef
179.
Okada Y, Feng Q, Lin Y, Jiang Q, Li Y, Coffield VM, Su L, Xu G, Zhang Y. hDOT1L links histone methylation to leukemogenesis. Cell. 2005;121:167–78.PubMedCrossRef
180.
Krivtsov AV, Feng Z, Lemieux ME, Faber J, Vempati S, Sinha AU, Xia X, Jesneck J, Bracken AP, Silverman LB, et al. H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell. 2008;14:355–68.PubMedPubMedCentralCrossRef
181.
Daigle SR, Olhava EJ, Therkelsen CA, Majer CR, Sneeringer CJ, Song J, Johnston LD, Scott MP, Smith JJ, Xiao Y, et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell. 2011;20:53–65.PubMedPubMedCentralCrossRef
182.
Daigle SR, Olhava EJ, Therkelsen CA, Basavapathruni A, Jin L, Boriack-Sjodin PA, Allain CJ, Klaus CR, Raimondi A, Scott MP, et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013;122:1017–25.PubMedPubMedCentralCrossRef
183.
Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002;298:1039–43.PubMedCrossRef
184.
Muller J, Hart CM, Francis NJ, Vargas ML, Sengupta A, Wild B, Miller EL, O’Connor MB, Kingston RE, Simon JA. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell. 2002;111:197–208.PubMedCrossRef
185.
Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev. 2002;16:2893–905.PubMedPubMedCentralCrossRef
186.
Wang X, Zhao H, Lv L, Bao L, Wang X, Han S. Prognostic Significance of EZH2 Expression in Non-Small Cell Lung Cancer: A Meta-analysis. Sci Rep. 2016;6:19239.PubMedPubMedCentralCrossRef
187.
Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci U S A. 2003;100:11606–11.PubMedPubMedCentralCrossRef
188.
Simon JA, Lange CA. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res. 2008;647:21–9.PubMedCrossRef
189.
Li Z, Wang Y, Qiu J, Li Q, Yuan C, Zhang W, Wang D, Ye J, Jiang H, Yang J, Cheng J. The polycomb group protein EZH2 is a novel therapeutic target in tongue cancer. Oncotarget. 2013;4:2532–49.PubMedPubMedCentralCrossRef
190.
Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002;419:624–9.PubMedCrossRef
191.
Weikert S, Christoph F, Kollermann J, Muller M, Schrader M, Miller K, Krause H. Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. Int J Mol Med. 2005;16:349–53.PubMed
192.
Shi J, Wang E, Zuber J, Rappaport A, Taylor M, Johns C, Lowe SW, Vakoc CR. The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;Nras(G12D) acute myeloid leukemia. Oncogene. 2013;32:930–8.PubMedCrossRef
193.
Suva ML, Riggi N, Janiszewska M, Radovanovic I, Provero P, Stehle JC, Baumer K, Le Bitoux MA, Marino D, Cironi L, et al. EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Res. 2009;69:9211–8.PubMedCrossRef
194.
Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 2006;20:1123–36.PubMedPubMedCentralCrossRef
195.
Miranda TB, Cortez CC, Yoo CB, Liang G, Abe M, Kelly TK, Marquez VE, Jones PA. DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol Cancer Ther. 2009;8:1579–88.PubMedPubMedCentralCrossRef
196.
Knutson SK, Warholic NM, Wigle TJ, Klaus CR, Allain CJ, Raimondi A, Porter Scott M, Chesworth R, Moyer MP, Copeland RA, et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc Natl Acad Sci U S A. 2013;110:7922–7.PubMedPubMedCentralCrossRef
197.
Knutson SK, Kawano S, Minoshima Y, Warholic NM, Huang KC, Xiao Y, Kadowaki T, Uesugi M, Kuznetsov G, Kumar N, et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol Cancer Ther. 2014;13:842–54.PubMedCrossRef
198.
McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, Liu Y, Graves AP, Della Pietra 3rd A, Diaz E, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012;492:108–12.PubMedCrossRef
199.
Chen YT, Zhu F, Lin WR, Ying RB, Yang YP, Zeng LH. The novel EZH2 inhibitor, GSK126, suppresses cell migration and angiogenesis via down-regulating VEGF-A. Cancer Chemother Pharmacol. 2016;77:757–65.PubMedCrossRef
200.
Van Aller GS, Pappalardi MB, Ott HM, Diaz E, Brandt M, Schwartz BJ, Miller WH, Dhanak D, McCabe MT, Verma SK, et al. Long residence time inhibition of EZH2 in activated polycomb repressive complex 2. ACS Chem Biol. 2014;9:622–9.PubMedCrossRef
201.
Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M, Fukuda M, Takeda N, Niida H, Kato H, Shinkai Y. G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 2002;16:1779–91.PubMedPubMedCentralCrossRef
202.
Huang J, Dorsey J, Chuikov S, Perez-Burgos L, Zhang X, Jenuwein T, Reinberg D, Berger SL. G9a and Glp methylate lysine 373 in the tumor suppressor p53. J Biol Chem. 2010;285:9636–41.PubMedPubMedCentralCrossRef
203.
Kondo Y, Shen L, Ahmed S, Boumber Y, Sekido Y, Haddad BR, Issa JP. Downregulation of histone H3 lysine 9 methyltransferase G9a induces centrosome disruption and chromosome instability in cancer cells. PLoS One. 2008;3:e2037.PubMedPubMedCentralCrossRef
204.
Kondo Y, Shen L, Suzuki S, Kurokawa T, Masuko K, Tanaka Y, Kato H, Mizuno Y, Yokoe M, Sugauchi F, et al. Alterations of DNA methylation and histone modifications contribute to gene silencing in hepatocellular carcinomas. Hepatol Res. 2007;37:974–83.PubMedCrossRef
205.
Chen MW, Hua KT, Kao HJ, Chi CC, Wei LH, Johansson G, Shiah SG, Chen PS, Jeng YM, Cheng TY, et al. H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM. Cancer Res. 2010;70:7830–40.PubMedCrossRef
206.
Cho HS, Kelly JD, Hayami S, Toyokawa G, Takawa M, Yoshimatsu M, Tsunoda T, Field HI, Neal DE, Ponder BA, et al. Enhanced expression of EHMT2 is involved in the proliferation of cancer cells through negative regulation of SIAH1. Neoplasia. 2011;13:676–84.PubMedPubMedCentralCrossRef
207.
Hua KT, Wang MY, Chen MW, Wei LH, Chen CK, Ko CH, Jeng YM, Sung PL, Jan YH, Hsiao M, et al. The H3K9 methyltransferase G9a is a marker of aggressive ovarian cancer that promotes peritoneal metastasis. Mol Cancer. 2014;13:189.PubMedPubMedCentralCrossRef
208.
Bai K, Cao Y, Huang C, Chen J, Zhang X, Jiang Y. Association of Histone Methyltransferase G9a and Overall Survival After Liver Resection of Patients With Hepatocellular Carcinoma With a Median Observation of 40 Months. Medicine (Baltimore). 2016;95:e2493.CrossRef
209.
Kubicek S, O’Sullivan RJ, August EM, Hickey ER, Zhang Q, Teodoro ML, Rea S, Mechtler K, Kowalski JA, Homon CA, et al. Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol Cell. 2007;25:473–81.PubMedCrossRef
210.
Trojer P, Zhang J, Yonezawa M, Schmidt A, Zheng H, Jenuwein T, Reinberg D. Dynamic Histone H1 Isotype 4 Methylation and Demethylation by Histone Lysine Methyltransferase G9a/KMT1C and the Jumonji Domain-containing JMJD2/KDM4 Proteins. J Biol Chem. 2009;284:8395–405.PubMedPubMedCentralCrossRef
211.
Maze I, Covington 3rd HE, Dietz DM, LaPlant Q, Renthal W, Russo SJ, Mechanic M, Mouzon E, Neve RL, Haggarty SJ, et al. Essential role of the histone methyltransferase G9a in cocaine-induced plasticity. Science. 2010;327:213–6.PubMedPubMedCentralCrossRef
212.
Kim Y, Kim YS, Kim DE, Lee JS, Song JH, Kim HG, Cho DH, Jeong SY, Jin DH, Jang SJ, et al. BIX-01294 induces autophagy-associated cell death via EHMT2/G9a dysfunction and intracellular reactive oxygen species production. Autophagy. 2013;9:2126–39.PubMedCrossRef
213.
Vedadi M, Barsyte-Lovejoy D, Liu F, Rival-Gervier S, Allali-Hassani A, Labrie V, Wigle TJ, Dimaggio PA, Wasney GA, Siarheyeva A, et al. A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nat Chem Biol. 2011;7:566–74.PubMedPubMedCentralCrossRef
214.
Liu F, Barsyte-Lovejoy D, Li F, Xiong Y, Korboukh V, Huang XP, Allali-Hassani A, Janzen WP, Roth BL, Frye SV, et al. Discovery of an in vivo chemical probe of the lysine methyltransferases G9a and GLP. J Med Chem. 2013;56:8931–42.PubMedCrossRef
215.
Lakshmikuttyamma A, Scott SA, DeCoteau JF, Geyer CR. Reexpression of epigenetically silenced AML tumor suppressor genes by SUV39H1 inhibition. Oncogene. 2010;29:576–88.PubMedCrossRef
216.
Devin J, Viziteu E, Herviou L, Seckinger A, Camille G, Goldschmidt H, Vincent L, Pasero P, Hose D, Klein B, Moreaux J. Inhibition of SUV39H Methyltransferase As a Potent Therapeutic Target in Multiple Myeloma. Blood. 2015;126:1771.
217.
Lai YS, Chen JY, Tsai HJ, Chen TY, Hung WC. The SUV39H1 inhibitor chaetocin induces differentiation and shows synergistic cytotoxicity with other epigenetic drugs in acute myeloid leukemia cells. Blood Cancer J. 2015;5:e313.PubMedPubMedCentralCrossRef
218.
Chiba T, Saito T, Yuki K, Zen Y, Koide S, Kanogawa N, Motoyama T, Ogasawara S, Suzuki E, Ooka Y, et al. Histone lysine methyltransferase SUV39H1 is a potent target for epigenetic therapy of hepatocellular carcinoma. Int J Cancer. 2015;136:289–98.PubMedCrossRef
219.
220.
Hojfeldt JW, Agger K, Helin K. Histone lysine demethylases as targets for anticancer therapy. Nat Rev Drug Discov. 2013;12:917–30.PubMedCrossRef
221.
Arrowsmith CH, Bountra C, Fish PV, Lee K, Schapira M. Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov. 2012;11:384–400.PubMedCrossRef
222.
Klose RJ, Kallin EM, Zhang Y. JmjC-domain-containing proteins and histone demethylation. Nat Rev Genet. 2006;7:715–27.PubMedCrossRef
223.
Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y, Ciceri F, Blaser JG, Greystoke BF, Jordan AM, et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell. 2012;21:473–87.PubMedCrossRef
224.
Konovalov S, Garcia-Bassets I. Analysis of the levels of lysine-specific demethylase 1 (LSD1) mRNA in human ovarian tumors and the effects of chemical LSD1 inhibitors in ovarian cancer cell lines. J Ovarian Res. 2013;6:75.PubMedPubMedCentralCrossRef
225.
Lynch JT, Harris WJ, Somervaille TC. LSD1 inhibition: a therapeutic strategy in cancer? Expert Opin Ther Targets. 2012;16:1239–49.PubMedCrossRef
226.
Schenk T, Chen WC, Gollner S, Howell L, Jin L, Hebestreit K, Klein HU, Popescu AC, Burnett A, Mills K, et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med. 2012;18:605–11.PubMedPubMedCentralCrossRef
227.
Maes T, Tirapu I, Mascaró C, Ortega A, Estiarte A, Valls N, Castro-Palomino J, Arjol CB, Kurz G. Preclinical characterization of a potent and selective inhibitor of the histone demethylase KDM1A for MLL leukemia. J Clin Oncol. 2013;31:e13543.
228.
Mohammad H, Smitheman K, Cusan M, Liu Y, Pappalardi M, Federowicz K, Van Aller G, Kasparec J, Tian X, Suarez D, et al. Inhibition Of LSD1 As a Therapeutic Strategy For The Treatment Of Acute Myeloid Leukemia. Blood. 2013;122:3964.CrossRef
229.
230.
Sprussel A, Schulte JH, Weber S, Necke M, Handschke K, Thor T, Pajtler KW, Schramm A, Konig K, Diehl L, et al. Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation. Leukemia. 2012;26:2039–51.PubMedCrossRef
231.
Mohammad HP, Smitheman KN, Kamat CD, Soong D, Federowicz KE, Van Aller GS, Schneck JL, Carson JD, Liu Y, Butticello M, et al. A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC. Cancer Cell. 2015;28:57–69.PubMedCrossRef
232.
Lan F, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, Iwase S, Alpatov R, Issaeva I, Canaani E, et al. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature. 2007;449:689–94.PubMedCrossRef
233.
Agger K, Cloos PA, Christensen J, Pasini D, Rose S, Rappsilber J, Issaeva I, Canaani E, Salcini AE, Helin K. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature. 2007;449:731–4.PubMedCrossRef
234.
Lee MG, Villa R, Trojer P, Norman J, Yan KP, Reinberg D, Di Croce L, Shiekhattar R. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science. 2007;318:447–50.PubMedCrossRef
235.
Issaeva I, Zonis Y, Rozovskaia T, Orlovsky K, Croce CM, Nakamura T, Mazo A, Eisenbach L, Canaani E. Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth. Mol Cell Biol. 2007;27:1889–903.PubMedCrossRef
236.
Cho YW, Hong T, Hong S, Guo H, Yu H, Kim D, Guszczynski T, Dressler GR, Copeland TD, Kalkum M, Ge K. PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. J Biol Chem. 2007;282:20395–406.PubMedPubMedCentralCrossRef
237.
Miller SA, Mohn SE, Weinmann AS. Jmjd3 and UTX play a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression. Mol Cell. 2010;40:594–605.PubMedPubMedCentralCrossRef
238.
Fu LL, Tian M, Li X, Li JJ, Huang J, Ouyang L, Zhang Y, Liu B. Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery. Oncotarget. 2015;6:5501–16.PubMedPubMedCentralCrossRef
239.
Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, et al. Selective inhibition of BET bromodomains. Nature. 2010;468:1067–73.PubMedPubMedCentralCrossRef
240.
Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146:904–17.PubMedPubMedCentralCrossRef
241.
Feng Q, Zhang Z, Shea MJ, Creighton CJ, Coarfa C, Hilsenbeck SG, Lanz R, He B, Wang L, Fu X, et al. An epigenomic approach to therapy for tamoxifen-resistant breast cancer. Cell Res. 2014;24:809–19.PubMedPubMedCentralCrossRef
242.
Rajagopalan V, Vaidyanathan M, Janardhanam VA, Bradner JE. Pre-clinical analysis of changes in intra-cellular biochemistry of glioblastoma multiforme (GBM) cells due to c-Myc silencing. Cell Mol Neurobiol. 2014;34:1059–69.PubMedCrossRef
243.
Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung CW, Chandwani R, Marazzi I, Wilson P, Coste H, et al. Suppression of inflammation by a synthetic histone mimic. Nature. 2010;468:1119–23.PubMedCrossRef
244.
Gosmini R, Nguyen VL, Toum J, Simon C, Brusq JM, Krysa G, Mirguet O, Riou-Eymard AM, Boursier EV, Trottet L, et al. The discovery of I-BET726 (GSK1324726A), a potent tetrahydroquinoline ApoA1 up-regulator and selective BET bromodomain inhibitor. J Med Chem. 2014;57:8111–31.PubMedCrossRef
245.
Garnier JM, Sharp PP, Burns CJ. BET bromodomain inhibitors: a patent review. Expert Opin Ther Pat. 2014;24:185–99.PubMedCrossRef
246.
Wyce A, Degenhardt Y, Bai Y, Le B, Korenchuk S, Crouthame MC, McHugh CF, Vessella R, Creasy CL, Tummino PJ, Barbash O. Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget. 2013;4:2419–29.PubMedPubMedCentralCrossRef
247.
Wyce A, Ganji G, Smitheman KN, Chung CW, Korenchuk S, Bai Y, Barbash O, Le B, Craggs PD, McCabe MT, et al. BET inhibition silences expression of MYCN and BCL2 and induces cytotoxicity in neuroblastoma tumor models. PLoS One. 2013;8:e72967.PubMedPubMedCentralCrossRef
248.
Herait PE, Berthon C, Thieblemont C, Raffoux E, Magarotto V, Stathis A, Thomas X, Leleu X, Gomez-Roca C, Odore E, et al. Abstract CT231: BET-bromodomain inhibitor OTX015 shows clinically meaningful activity at nontoxic doses: interim results of an ongoing phase I trial in hematologic malignancies. Cancer Res. 2014;74:CT231.CrossRef
249.
Bonetti P, Ponzoni M, Tibiletti MG, Stathis A, Heirat P, Zucca E, Bertoni F. 528 The BRD-inhibitor OTX015 Shows Pre-clinical Activity in Diffuse Large B-cell Lymphoma (DLBCL). Eur J Cancer. 2012;48:163.
250.
Chaidos A, Caputo V, Gouvedenou K, Liu B, Marigo I, Chaudhry MS, Rotolo A, Tough DF, Smithers NN, Bassil AK, et al. Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762. Blood. 2014;123:697–705.PubMedCrossRef
251.
Pathania R, Ramachandran S, Mariappan G, Thakur P, Shi H, Choi J-H, Manicassamy S, Kolhe R, Prasad PD, Sharma S, et al. Combined inhibition of DNMT and HDAC blocks the tumorigenicity of cancer stem-like cells and attenuates mammary tumor growth. Cancer Res. 2016;76:3224–35.PubMedCrossRef
252.
Juergens RA, Wrangle J, Vendetti FP, Murphy SC, Zhao M, Coleman B, Sebree R, Rodgers K, Hooker CM, Franco N, et al. Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 2011;1:598–607.PubMedPubMedCentralCrossRef
253.
Ecke I, Petry F, Rosenberger A, Tauber S, Monkemeyer S, Hess I, Dullin C, Kimmina S, Pirngruber J, Johnsen SA, et al. Antitumor effects of a combined 5-aza-2’deoxycytidine and valproic acid treatment on rhabdomyosarcoma and medulloblastoma in Ptch mutant mice. Cancer Res. 2009;69:887–95.PubMedCrossRef
254.
Curry E, Green I, Chapman-Rothe N, Shamsaei E, Kandil S, Cherblanc FL, Payne L, Bell E, Ganesh T, Srimongkolpithak N, et al. Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells. Clin Epigenetics. 2015;7:84.PubMedPubMedCentralCrossRef
255.
Klaus CR, Iwanowicz D, Johnston D, Campbell CA, Smith JJ, Moyer MP, Copeland RA, Olhava EJ, Scott MP, Pollock RM, et al. DOT1L inhibitor EPZ-5676 displays synergistic antiproliferative activity in combination with standard of care drugs and hypomethylating agents in MLL-rearranged leukemia cells. J Pharmacol Exp Ther. 2014;350:646–56.PubMedCrossRef
256.
Easwaran H, Tsai HC, Baylin SB. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell. 2014;54:716–27.PubMedPubMedCentralCrossRef
257.
Vatapalli RJ, Guzzetta AA, Fu T, Syed LH, Kwak R, Ahuja N. Improving Sensitivity to Irinotecan Using 5-Azacytidine in Colon Cancer Cell Lines. J Surgical Res. 2013;179:251–252.
258.
Fu S, Hu W, Iyer R, Kavanagh JJ, Coleman RL, Levenback CF, Sood AK, Wolf JK, Gershenson DM, Markman M, et al. Phase 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer. Cancer. 2011;117:1661–9.PubMedCrossRef
259.
Appleton K, Mackay HJ, Judson I, Plumb JA, McCormick C, Strathdee G, Lee C, Barrett S, Reade S, Jadayel D, et al. Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J Clin Oncol. 2007;25:4603–9.PubMedCrossRef
260.
Matei D, Fang F, Shen C, Schilder J, Arnold A, Zeng Y, Berry WA, Huang T, Nephew KP. Epigenetic resensitization to platinum in ovarian cancer. Cancer Res. 2012;72:2197–205.PubMedPubMedCentralCrossRef
261.
Ramaswamy B, Fiskus W, Cohen B, Pellegrino C, Hershman DL, Chuang E, Luu T, Somlo G, Goetz M, Swaby R, et al. Phase I-II study of vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer: evidence for vorinostat-induced tubulin acetylation and Hsp90 inhibition in vivo. Breast Cancer Res Treat. 2012;132:1063–72.PubMedCrossRef
262.
Li SY, Sun R, Wang HX, Shen S, Liu Y, Du XJ, Zhu YH, Jun W. Combination therapy with epigenetic-targeted and chemotherapeutic drugs delivered by nanoparticles to enhance the chemotherapy response and overcome resistance by breast cancer stem cells. J Control Release. 2015;205:7–14.PubMedCrossRef
263.
264.
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.PubMedPubMedCentralCrossRef
265.
Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother. 2005;54:307–14.PubMedCrossRef
266.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.PubMedPubMedCentralCrossRef
267.
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.PubMedPubMedCentralCrossRef
268.
Pan Q, Li Q, Liu S, Ning N, Zhang X, Xu Y, Chang AE, Wicha MS. Concise Review: Targeting Cancer Stem Cells Using Immunologic Approaches. Stem Cells. 2015;33:2085–92.PubMedPubMedCentralCrossRef
269.
Covre A, Coral S, Nicolay H, Parisi G, Fazio C, Colizzi F, Fratta E, Di Giacomo AM, Sigalotti L, Natali PG, Maio M. Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models. Oncoimmunology. 2015;4:e1019978.PubMedPubMedCentralCrossRef
270.
Kim K, Skora AD, Li Z, Liu Q, Tam AJ, Blosser RL, Diaz Jr LA, Papadopoulos N, Kinzler KW, Vogelstein B, Zhou S. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci U S A. 2014;111:11774–9.PubMedPubMedCentralCrossRef
271.
Qifeng S, Bo C, Xingtao J, Chuanliang P, Xiaogang Z. Methylation of the promoter of human leukocyte antigen class I in human esophageal squamous cell carcinoma and its histopathological characteristics. J Thorac Cardiovasc Surg. 2011;141:808–14.PubMedCrossRef
272.
Ye Q, Shen Y, Wang X, Yang J, Miao F, Shen C, Zhang J. Hypermethylation of HLA class I gene is associated with HLA class I down-regulation in human gastric cancer. Tissue Antigens. 2010;75:30–9.PubMedCrossRef
273.
Kitamura H, Torigoe T, Asanuma H, Honma I, Sato N, Tsukamoto T. Down-regulation of HLA class I antigens in prostate cancer tissues and up-regulation by histone deacetylase inhibition. J Urol. 2007;178:692–6.PubMedCrossRef
274.
Magner WJ, Kazim AL, Stewart C, Romano MA, Catalano G, Grande C, Keiser N, Santaniello F, Tomasi TB. Activation of MHC class I, II, and CD40 gene expression by histone deacetylase inhibitors. J Immunol. 2000;165:7017–24.PubMedCrossRef
275.
Mora-Garcia Mde L, Duenas-Gonzalez A, Hernandez-Montes J, De la Cruz-Hernandez E, Perez-Cardenas E, Weiss-Steider B, Santiago-Osorio E, Ortiz-Navarrete VF, Rosales VH, Cantu D, et al. Up-regulation of HLA class-I antigen expression and antigen-specific CTL response in cervical cancer cells by the demethylating agent hydralazine and the histone deacetylase inhibitor valproic acid. J Transl Med. 2006;4:55.PubMedCrossRef
276.
Li H, Chiappinelli KB, Guzzetta AA, Easwaran H, Yen RW, Vatapalli R, Topper MJ, Luo J, Connolly RM, Azad NS, et al. Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget. 2014;5:587–98.PubMedPubMedCentralCrossRef
277.
Azad N, Zahnow CA, Rudin CM, Baylin SB. The future of epigenetic therapy in solid tumours--lessons from the past. Nat Rev Clin Oncol. 2013;10:256–66.PubMedPubMedCentralCrossRef
278.
Silverman LR, Fenaux P, Mufti GJ, Santini V, Hellstrom-Lindberg E, Gattermann N, Sanz G, List AF, Gore SD, Seymour JF. Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Cancer. 2011;117:2697–702.PubMedPubMedCentralCrossRef
279.
Griffiths EA, Choy G, Redkar S, Taverna P, Azab M, Karpf AR. SGI-110: DNA Methyltransferase Inhibitor Oncolytic. Drugs Future. 2013;38:535–43.PubMedPubMedCentral
280.
Issa JP, Roboz G, Rizzieri D, Jabbour E, Stock W, O’Connell C, Yee K, Tibes R, Griffiths EA, Walsh K, et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol. 2015;16:1099–110.PubMedCrossRef
281.
Fang F, Munck J, Tang J, Taverna P, Wang Y, Miller DF, Pilrose J, Choy G, Azab M, Pawelczak KS, et al. The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. Clin Cancer Res. 2014;20:6504–16.PubMedPubMedCentralCrossRef
282.
Younes A, Sureda A, Ben-Yehuda D, Zinzani PL, Ong TC, Prince HM, Harrison SJ, Kirschbaum M, Johnston P, Gallagher J, et al. Panobinostat in patients with relapsed/refractory Hodgkin’s lymphoma after autologous stem-cell transplantation: results of a phase II study. J Clin Oncol. 2012;30:2197–203.PubMedCrossRef
283.
Duvic M, Dummer R, Becker JC, Poulalhon N, Ortiz Romero P, Grazia Bernengo M, Lebbe C, Assaf C, Squier M, Williams D, et al. Panobinostat activity in both bexarotene-exposed and -naive patients with refractory cutaneous T-cell lymphoma: results of a phase II trial. Eur J Cancer. 2013;49:386–94.PubMedCrossRef
284.
Batlevi CL, Kasamon Y, Bociek RG, Lee P, Gore L, Copeland A, Sorensen R, Ordentlich P, Cruickshank S, Kunkel L, et al. ENGAGE- 501: phase II study of entinostat (SNDX-275) in relapsed and refractory Hodgkin lymphoma. Haematologica. 2016;101:968–75.PubMedPubMedCentralCrossRef
285.
Kirschbaum MH, Foon KA, Frankel P, Ruel C, Pulone B, Tuscano JM, Newman EM. A phase 2 study of belinostat (PXD101) in patients with relapsed or refractory acute myeloid leukemia or patients over the age of 60 with newly diagnosed acute myeloid leukemia: a California Cancer Consortium Study. Leuk Lymphoma. 2014;55:2301–4.PubMedPubMedCentralCrossRef
286.
O’Connor OA, Horwitz S, Masszi T, Van Hoof A, Brown P, Doorduijn J, Hess G, Jurczak W, Knoblauch P, Chawla S, et al. Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results of the Pivotal Phase II BELIEF (CLN-19) Study. J Clin Oncol. 2015;33:2492–9.PubMedPubMedCentralCrossRef
287.
Mackay HJ, Hirte H, Colgan T, Covens A, MacAlpine K, Grenci P, Wang L, Mason J, Pham PA, Tsao MS, et al. Phase II trial of the histone deacetylase inhibitor belinostat in women with platinum resistant epithelial ovarian cancer and micropapillary (LMP) ovarian tumours. Eur J Cancer. 2010;46:1573–9.PubMedPubMedCentralCrossRef
288.
Chu QS, Nielsen TO, Alcindor T, Gupta A, Endo M, Goytain A, Xu H, Verma S, Tozer R, Knowling M, et al. A phase II study of SB939, a novel pan-histone deacetylase inhibitor, in patients with translocation-associated recurrent/metastatic sarcomas-NCIC-CTG IND 200dagger. Ann Oncol. 2015;26:973–81.PubMedCrossRef
289.
Eigl BJ, North S, Winquist E, Finch D, Wood L, Sridhar SS, Powers J, Good J, Sharma M, Squire JA, et al. A phase II study of the HDAC inhibitor SB939 in patients with castration resistant prostate cancer: NCIC clinical trials group study IND195. Invest New Drugs. 2015;33:969–76.PubMedCrossRef
290.
Rambaldi A, Dellacasa CM, Finazzi G, Carobbio A, Ferrari ML, Guglielmelli P, Gattoni E, Salmoiraghi S, Finazzi MC, Di Tollo S, et al. A pilot study of the Histone-Deacetylase inhibitor Givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms. Br J Haematol. 2010;150:446–55.PubMed
291.
Mawatari T, Ninomiya I, Inokuchi M, Harada S, Hayashi H, Oyama K, Makino I, Nakagawara H, Miyashita T, Tajima H, et al. Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation. Int J Oncol. 2015;47:2073–81.PubMedPubMedCentral
292.
Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, Karuturi RK, Tan PB, Liu ET, Yu Q. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 2007;21:1050–63.PubMedPubMedCentralCrossRef
293.
Crea F, Hurt EM, Mathews LA, Cabarcas SM, Sun L, Marquez VE, Danesi R, Farrar WL. Pharmacologic disruption of Polycomb Repressive Complex 2 inhibits tumorigenicity and tumor progression in prostate cancer. Mol Cancer. 2011;10:40.PubMedPubMedCentralCrossRef
294.
Bradley WD, Arora S, Busby J, Balasubramanian S, Gehling VS, Nasveschuk CG, Vaswani RG, Yuan CC, Hatton C, Zhao F, et al. EZH2 inhibitor efficacy in non-Hodgkin’s lymphoma does not require suppression of H3K27 monomethylation. Chem Biol. 2014;21:1463–75.PubMedCrossRef
295.
Kruidenier L, Chung CW, Cheng Z, Liddle J, Che K, Joberty G, Bantscheff M, Bountra C, Bridges A, Diallo H, et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature. 2012;488:404–8.PubMedPubMedCentralCrossRef
296.
Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, Mele DA, Bergeron L, Sims 3rd RJ. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A. 2011;108:16669–74.PubMedPubMedCentralCrossRef
297.
Chapuy B, McKeown MR, Lin CY, Monti S, Roemer MG, Qi J, Rahl PB, Sun HH, Yeda KT, Doench JG, et al. Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma. Cancer Cell. 2013;24:777–90.PubMedPubMedCentralCrossRef
298.
Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M, Chan WI, Robson SC, Chung CW, Hopf C, Savitski MM, et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011;478:529–33.PubMedPubMedCentralCrossRef
299.
Long J, Li B, Rodriguez-Blanco J, Pastori C, Volmar CH, Wahlestedt C, Capobianco A, Bai F, Pei XH, Ayad NG, Robbins DJ. The BET bromodomain inhibitor I-BET151 acts downstream of smoothened protein to abrogate the growth of hedgehog protein-driven cancers. J Biol Chem. 2014;289:35494–502.PubMedPubMedCentralCrossRef
300.
Moros A, Rodriguez V, Saborit-Villarroya I, Montraveta A, Balsas P, Sandy P, Martinez A, Wiestner A, Normant E, Campo E, et al. Synergistic antitumor activity of lenalidomide with the BET bromodomain inhibitor CPI203 in bortezomib-resistant mantle cell lymphoma. Leukemia. 2014;28:2049–59.PubMed
301.
Albrecht BK, Gehling VS, Hewitt MC, Vaswani RG, Cote A, Leblanc Y, Nasveschuk CG, Bellon S, Bergeron L, Campbell R, et al. Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials. J Med Chem. 2016;59:1330–9.PubMedCrossRef
Metadata
Title
Epigenetics in cancer stem cells
Authors
Tan Boon Toh
Jhin Jieh Lim
Edward Kai-Hua Chow
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2017
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-017-0596-9

Other articles of this Issue 1/2017

Molecular Cancer 1/2017 Go to the issue

Research

A novel mechanism of lncRNA and miRNA interaction: CCAT2 regulates miR-145 expression by suppressing its maturation process in colon cancer cells

Review

Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development

Research

SOX2 regulates multiple malignant processes of breast cancer development through the SOX2/miR-181a-5p, miR-30e-5p/TUSC3 axis

Research

Exosomes derived from gemcitabine-resistant cells transfer malignant phenotypic traits via delivery of miRNA-222-3p

Letter to the Editor

Dual role for p16 in the metastasis process of HPV positive head and neck cancers

Research

Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits