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 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2016

Open Access 01-12-2016 | Review

Targeting histone methylation for cancer therapy: enzymes, inhibitors, biological activity and perspectives

Authors: Yongcheng Song, Fangrui Wu, Jingyu Wu

Published in: Journal of Hematology & Oncology | Issue 1/2016

Login to get access

Abstract

Post-translational methylation of histone lysine or arginine residues plays important roles in gene regulation and other physiological processes. Aberrant histone methylation caused by a gene mutation, translocation, or overexpression can often lead to initiation of a disease such as cancer. Small molecule inhibitors of such histone modifying enzymes that correct the abnormal methylation could be used as novel therapeutics for these diseases, or as chemical probes for investigation of epigenetics. Discovery and development of histone methylation modulators are in an early stage and undergo a rapid expansion in the past few years. A number of highly potent and selective compounds have been reported, together with extensive preclinical studies of their biological activity. Several compounds have been in clinical trials for safety, pharmacokinetics, and efficacy, targeting several types of cancer. This review summarizes the biochemistry, structures, and biology of cancer-relevant histone methylation modifying enzymes, small molecule inhibitors and their preclinical and clinical antitumor activities. Perspectives for targeting histone methylation for cancer therapy are also discussed.
Literature
1.
2.
3.
Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006;6(1):38–51.PubMedCrossRef
4.
Copeland RA, Solomon ME, Richon VM. Protein methyltransferases as a target class for drug discovery. Nat Rev Drug Discov. 2009;8(9):724–32.PubMedCrossRef
5.
Miller TA, Witter DJ, Belvedere S. Histone deacetylase inhibitors. J Med Chem. 2003;46(24):5097–116.PubMedCrossRef
6.
7.
Zheng Z, Cheng S, Wu W, Wang L, Zhao Y, Shen Y, et al. c-FLIP is involved in tumor progression of peripheral T-cell lymphoma and targeted by histone deacetylase inhibitors. J Hematol Oncol. 2014;7:88.PubMedPubMedCentralCrossRef
8.
Bhaumik SR, Smith E, Shilatifard A. Covalent modifications of histones during development and disease pathogenesis. Nat Struct Mol Biol. 2007;14(11):1008–16.PubMedCrossRef
9.
Cheng X, Collins RE, Zhang X. Structural and sequence motifs of protein (histone) methylation enzymes. Annu Rev Biophys Biomol Struct. 2005;34:267–94.PubMedPubMedCentralCrossRef
10.
11.
12.
Hojfeldt JW, Agger K, Helin K. Histone lysine demethylases as targets for anticancer therapy. Nat Rev Drug Discov. 2013;12(12):917–30.PubMedCrossRef
13.
Cloos PA, Christensen J, Agger K, Helin K. Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. Genes Dev. 2008;22(9):1115–40.PubMedPubMedCentralCrossRef
14.
15.
Liu Y, Liu K, Qin S, Xu C, Min J. Epigenetic targets and drug discovery: part 1: histone methylation. Pharmacol Ther. 2014;143(3):275–94.PubMedCrossRef
16.
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
17.
McGrath J, Trojer P. Targeting histone lysine methylation in cancer. Pharmacol Ther. 2015;150:1–22.PubMedCrossRef
18.
Richon VM, Johnston D, Sneeringer CJ, Jin L, Majer CR, Elliston K, et al. Chemogenetic analysis of human protein methyltransferases. Chem Biol Drug Des. 2011;78(2):199–210.PubMedCrossRef
19.
20.
Min J, Feng Q, Li Z, Zhang Y, Xu RM. Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase. Cell. 2003;112(5):711–23.PubMedCrossRef
21.
Liu F, Chen X, Allali-Hassani A, Quinn AM, Wasney GA, Dong A, et al. Discovery of a 2,4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a. J Med Chem. 2009;52(24):7950–3.PubMedPubMedCentralCrossRef
22.
Binda C, Valente S, Romanenghi M, Pilotto S, Cirilli R, Karytinos A, et al. Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2. J Am Chem Soc. 2010;132(19):6827–33.PubMedCrossRef
23.
Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004;119(7):941–53.PubMedCrossRef
24.
Forneris F, Binda C, Adamo A, Battaglioli E, Mattevi A. Structural basis of LSD1-CoREST selectivity in histone H3 recognition. J Biol Chem. 2007;282(28):20070–4.PubMedCrossRef
25.
Pedersen MT, Helin K. Histone demethylases in development and disease. Trends Cell Biol. 2010;20(11):662–71.PubMedCrossRef
26.
Maes T, Carceller E, Salas J, Ortega A, Buesa C. Advances in the development of histone lysine demethylase inhibitors. Curr Opin Pharmacol. 2015;23:52–60.PubMedCrossRef
27.
Schneider J, Shilatifard A. Histone demethylation by hydroxylation: chemistry in action. ACS Chem Biol. 2006;1(2):75–81.PubMedCrossRef
28.
Chen Z, Zang J, Kappler J, Hong X, Crawford F, Wang Q, et al. Structural basis of the recognition of a methylated histone tail by JMJD2A. Proc Natl Acad Sci U S A. 2007;104(26):10818–23.PubMedPubMedCentralCrossRef
29.
Horton JR, Upadhyay AK, Qi HH, Zhang X, Shi Y, Cheng X. Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases. Nat Struct Mol Biol. 2010;17(1):38–43.PubMedCrossRef
30.
Singer MS, Kahana A, Wolf AJ, Meisinger LL, Peterson SE, Goggin C, et al. Identification of high-copy disruptors of telomeric silencing in Saccharomyces cerevisiae. Genetics. 1998;150(2):613–32.PubMedPubMedCentral
31.
Feng Q, Wang H, Ng HH, Erdjument-Bromage H, Tempst P, Struhl K, et al. Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain. Curr Biol. 2002;12(12):1052–8.PubMedCrossRef
32.
Mueller D, Bach C, Zeisig D, Garcia-Cuellar MP, Monroe S, Sreekumar A, et al. A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood. 2007;110(13):4445–54.PubMedPubMedCentralCrossRef
33.
Mueller D, Garcia-Cuellar MP, Bach C, Buhl S, Maethner E, Slany RK. Misguided transcriptional elongation causes mixed lineage leukemia. PLoS Biol. 2009;7(11):e1000249.PubMedPubMedCentralCrossRef
34.
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(1):92–106.PubMedCrossRef
35.
Mohan M, Herz HM, Takahashi YH, Lin C, Lai KC, Zhang Y, et al. Linking H3K79 trimethylation to Wnt signaling through a novel Dot1-containing complex (DotCom). Genes Dev. 2010;24(6):574–89.PubMedPubMedCentralCrossRef
36.
Lin C, Smith ER, Takahashi H, Lai KC, Martin-Brown S, Florens L, et al. AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol Cell. 2010;37(3):429–37.PubMedPubMedCentralCrossRef
37.
38.
Barry ER, Corry GN, Rasmussen TP. Targeting DOT1L action and interactions in leukemia: the role of DOT1L in transformation and development. Expert Opin Ther Targets. 2010;14(4):405–18.PubMedCrossRef
39.
Bernt KM, Armstrong SA. A role for DOT1L in MLL-rearranged leukemias. Epigenomics. 2011;3(6):667–70.PubMedCrossRef
40.
41.
van Leeuwen F, Gafken PR, Gottschling DE. Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell. 2002;109(6):745–56.PubMedCrossRef
42.
Steger DJ, Lefterova MI, Ying L, Stonestrom AJ, Schupp M, Zhuo D, et al. DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells. Mol Cell Biol. 2008;28(8):2825–39.PubMedPubMedCentralCrossRef
43.
Wang Z, Zang C, Rosenfeld JA, Schones DE, Barski A, Cuddapah S, et al. Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genet. 2008;40(7):897–903.PubMedPubMedCentralCrossRef
44.
Shanower GA, Muller M, Blanton JL, Honti V, Gyurkovics H, Schedl P. Characterization of the grappa gene, the Drosophila histone H3 lysine 79 methyltransferase. Genetics. 2005;169(1):173–84.PubMedPubMedCentralCrossRef
45.
Ooga M, Inoue A, Kageyama S, Akiyama T, Nagata M, Aoki F. Changes in H3K79 methylation during preimplantation development in mice. Biol Reprod. 2008;78(3):413–24.PubMedCrossRef
46.
Jones B, Su H, Bhat A, Lei H, Bajko J, Hevi S, et al. The histone H3K79 methyltransferase Dot1L is essential for mammalian development and heterochromatin structure. PLoS Genet. 2008;4(9):e1000190.PubMedPubMedCentralCrossRef
47.
48.
Feng Y, Yang Y, Ortega MM, Copeland JN, Zhang M, Jacob JB, et al. Early mammalian erythropoiesis requires the Dot1L methyltransferase. Blood. 2010;116(22):4483–91.PubMedPubMedCentralCrossRef
49.
Nguyen AT, Xiao B, Neppl RL, Kallin EM, Li J, Chen T, et al. DOT1L regulates dystrophin expression and is critical for cardiac function. Genes Dev. 2011;25(3):263–74.PubMedPubMedCentralCrossRef
50.
Reisenauer MR, Wang SW, Xia Y, Zhang W. Dot1a contains three nuclear localization signals and regulates the epithelial Na+ channel (ENaC) at multiple levels. Am J Physiol Renal Physiol. 2010;299(1):F63–76.PubMedPubMedCentralCrossRef
51.
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(26):18059–68.PubMedPubMedCentralCrossRef
52.
Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nature reviews. 2007;7(11):823–33.PubMed
53.
Daser A, Rabbitts TH. The versatile mixed lineage leukaemia gene MLL and its many associations in leukaemogenesis. Semin Cancer Biol. 2005;15(3):175–88.PubMedCrossRef
54.
55.
Hilden JM, Dinndorf PA, Meerbaum SO, Sather H, Villaluna D, Heerema NA, et al. Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children's Oncology Group. Blood. 2006;108(2):441–51.PubMedPubMedCentralCrossRef
56.
Chen CS, Sorensen PH, Domer PH, Reaman GH, Korsmeyer SJ, Heerema NA, et al. Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood. 1993;81(9):2386–93.PubMed
57.
Felix CA, Hosler MR, Winick NJ, Masterson M, Wilson AE, Lange BJ. ALL-1 gene rearrangements in DNA topoisomerase II inhibitor-related leukemia in children. Blood. 1995;85(11):3250–6.PubMed
58.
Mrozek K, Heinonen K, Lawrence D, Carroll AJ, Koduru PR, Rao KW, et al. Adult patients with de novo acute myeloid leukemia and t(9; 11)(p22; q23) have a superior outcome to patients with other translocations involving band 11q23: a cancer and leukemia group B study. Blood. 1997;90(11):4532–8.PubMed
59.
Ross ME, Mahfouz R, Onciu M, Liu H-C, Zhou X, Song G, et al. Gene expression profiling of pediatric acute myelogenous leukemia. Blood. 2004;104(12):3679–87.PubMedCrossRef
60.
Gu Y, Nakamura T, Alder H, Prasad R, Canaani O, Cimino G, et al. The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell. 1992;71(4):701–8.PubMedCrossRef
61.
Tkachuk DC, Kohler S, Cleary ML. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell. 1992;71(4):691–700.PubMedCrossRef
62.
Butler LH, Slany R, Cui X, Cleary ML, Mason DY. The HRX proto-oncogene product is widely expressed in human tissues and localizes to nuclear structures. Blood. 1997;89(9):3361–70.PubMed
63.
Briggs SD, Bryk M, Strahl BD, Cheung WL, Davie JK, Dent SY, et al. Histone H3 lysine 4 methylation is mediated by Set1 and required for cell growth and rDNA silencing in Saccharomyces cerevisiae. Genes Dev. 2001;15(24):3286–95.PubMedPubMedCentralCrossRef
64.
Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, Allis CD, et al. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell. 2002;10(5):1107–17.PubMedCrossRef
65.
Ayton PM, Cleary ML. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene. 2001;20(40):5695–707.PubMedCrossRef
66.
Okada Y, Feng Q, Lin Y, Jiang Q, Li Y, Coffield VM, et al. hDOT1L links histone methylation to leukemogenesis. Cell. 2005;121(2):167–78.PubMedCrossRef
67.
Krivtsov AV, Feng Z, Lemieux ME, Faber J, Vempati S, Sinha AU, et al. H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell. 2008;14(5):355–68.PubMedPubMedCentralCrossRef
68.
Daigle SR, Olhava EJ, Therkelsen CA, Majer CR, Sneeringer CJ, Song J, et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell. 2011;20(1):53–65.PubMedPubMedCentralCrossRef
69.
Basavapathruni A, Jin L, Daigle SR, Majer CR, Therkelsen CA, Wigle TJ, et al. Conformational adaptation drives potent, selective and durable inhibition of the human protein methyltransferase DOT1L. Chem Biol Drug Des. 2012;80(6):971–80.PubMedCrossRef
70.
Anglin JL, Deng L, Yao Y, Cai G, Liu Z, Jiang H, et al. Synthesis and structure-activity relationship investigation of adenosine-containing inhibitors of histone methyltransferase DOT1L. J Med Chem. 2012;55(18):8066–74.PubMedPubMedCentralCrossRef
71.
Yao Y, Chen P, Diao J, Cheng G, Deng L, Anglin JL, et al. Selective inhibitors of histone methyltransferase DOT1L: design, synthesis, and crystallographic studies. J Am Chem Soc. 2011;133(42):16746–9.PubMedPubMedCentralCrossRef
72.
Yu W, Smil D, Li F, Tempel W, Fedorov O, Nguyen KT, et al. Bromo-deaza-SAH: a potent and selective DOT1L inhibitor. Bioorg Med Chem. 2013;21(7):1787–94.PubMedPubMedCentralCrossRef
73.
Daigle SR, Olhava EJ, Therkelsen CA, Basavapathruni A, Jin L, Boriack-Sjodin PA, et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013;122(6):1017–25.PubMedPubMedCentralCrossRef
74.
75.
Deng L, Zhang L, Yao Y, Wang C, Redell MS, Dong S, et al. Synthesis, Activity and Metabolic Stability of Non-Ribose Containing Inhibitors of Histone Methyltransferase DOT1L. Med Chem Commun. 2013;4(5):822–6.CrossRef
76.
Yu W, Chory EJ, Wernimont AK, Tempel W, Scopton A, Federation A, et al. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat Commun. 2012;3:1288.PubMedCrossRef
77.
Stein E, Garcia-Manero G, Rizzieri DA, Savona M, Tibes R, Altman JK, Jongen-Lavrencic M, Döhner H, Armstrong S, Pollock RM, Waters N, Legler M, Thomson B, Daigle S, McDonald A, Campbell C, Olhava E, Hedrick EE, Lowenberg B, Copeland RA, Tallman MS: The DOT1L Inhibitor EPZ-5676: Safety and Activity in Relapsed/Refractory Patients with MLL-Rearranged Leukemia. In: 56th ASH Annual Meeting and Exposition: 2014; San Francisco, CA.
78.
Zhang L, Deng L, Chen F, Yao Y, Wu B, Wei L, et al. Inhibition of histone H3K79 methylation selectively inhibits proliferation, self-renewal and metastatic potential of breast cancer. Oncotarget. 2014;5(21):10665–77.PubMedPubMedCentralCrossRef
79.
Kim W, Kim R, Park G, Park JW, Kim JE. Deficiency of H3K79 histone methyltransferase Dot1-like protein (DOT1L) inhibits cell proliferation. J Biol Chem. 2012;287(8):5588–99.PubMedCrossRef
80.
Onder TT, Kara N, Cherry A, Sinha AU, Zhu N, Bernt KM, et al. Chromatin-modifying enzymes as modulators of reprogramming. Nature. 2012;483(7391):598–602.PubMedPubMedCentralCrossRef
81.
Guenther MG, Jenner RG, Chevalier B, Nakamura T, Croce CM, Canaani E, et al. Global and Hox-specific roles for the MLL1 methyltransferase. Proc Natl Acad Sci U S A. 2005;102(24):8603–8.PubMedPubMedCentralCrossRef
82.
Zeleznik-Le NJ, Harden AM, Rowley JD. 11q23 translocations split the "AT-hook" cruciform DNA-binding region and the transcriptional repression domain from the activation domain of the mixed-lineage leukemia (MLL) gene. Proc Natl Acad Sci U S A. 1994;91(22):10610–4.PubMedPubMedCentralCrossRef
83.
Abramovich C, Humphries RK. Hox regulation of normal and leukemic hematopoietic stem cells. Curr Opin Hematol. 2005;12(3):210–6.PubMedCrossRef
84.
Thiel AT, Blessington P, Zou T, Feather D, Wu X, Yan J, et al. MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele. Cancer Cell. 2010;17(2):148–59.PubMedPubMedCentralCrossRef
85.
Stavropoulos P, Blobel G, Hoelz A. Crystal structure and mechanism of human lysine-specific demethylase-1. Nat Struct Mol Biol. 2006;13(7):626–32.PubMedCrossRef
86.
Kerenyi MA, Shao Z, Hsu YJ, Guo G, Luc S, O'Brien K, et al. Histone demethylase Lsd1 represses hematopoietic stem and progenitor cell signatures during blood cell maturation. eLife. 2013;2:e00633.PubMedPubMedCentralCrossRef
87.
Nakamura T, Mori T, Tada S, Krajewski W, Rozovskaia T, Wassell R, et al. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol Cell. 2002;10(5):1119–28.PubMedCrossRef
88.
Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y, et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell. 2012;21(4):473–87.PubMedCrossRef
89.
90.
Lynch JT, Harris WJ, Somervaille TC. LSD1 inhibition: a therapeutic strategy in cancer? Expert Opin Ther Targets. 2012;16(12):1239–49.PubMedCrossRef
91.
Sprussel A, Schulte JH, Weber S, Necke M, Handschke K, Thor T, et al. Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation. Leukemia. 2012;26(9):2039–51.PubMedCrossRef
92.
Metzger E, Wissmann M, Yin N, Muller JM, Schneider R, Peters AH, et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature. 2005;437(7057):436–9.PubMed
93.
Wang J, Hevi S, Kurash JK, Lei H, Gay F, Bajko J, et al. The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat Genet. 2009;41(1):125–9.PubMedCrossRef
94.
Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA, Richter M, et al. p53 is regulated by the lysine demethylase LSD1. Nature. 2007;449(7158):105–8.PubMedCrossRef
95.
Cho HS, Suzuki T, Dohmae N, Hayami S, Unoki M, Yoshimatsu M, et al. Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells. Cancer Res. 2011;71(3):655–60.PubMedCrossRef
96.
Yang J, Huang J, Dasgupta M, Sears N, Miyagi M, Wang B, et al. Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes. Proc Natl Acad Sci U S A. 2010;107(50):21499–504.PubMedPubMedCentralCrossRef
97.
Liu X, Jia X, Yuan H, Ma K, Chen Y, Jin Y, et al. DNA methyltransferase 1 functions through C/ebpa to maintain hematopoietic stem and progenitor cells in zebrafish. J Hematol Oncol. 2015;8:15.PubMedPubMedCentralCrossRef
98.
Goardon N, Marchi E, Atzberger A, Quek L, Schuh A, Soneji S, et al. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell. 2011;19(1):138–52.PubMedCrossRef
99.
Berglund L, Bjorling E, Oksvold P, Fagerberg L, Asplund A, Szigyarto CA, et al. A genecentric Human Protein Atlas for expression profiles based on antibodies. Mol Cell Proteomics. 2008;7(10):2019–27.PubMedCrossRef
100.
Kahl P, Gullotti L, Heukamp LC, Wolf S, Friedrichs N, Vorreuther R, et al. Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence. Cancer Res. 2006;66(23):11341–7.PubMedCrossRef
101.
Lim S, Janzer A, Becker A, Zimmer A, Schule R, Buettner R, et al. Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology. Carcinogenesis. 2010;31(3):512–20.PubMedCrossRef
102.
Schulte JH, Lim S, Schramm A, Friedrichs N, Koster J, Versteeg R, et al. Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res. 2009;69(5):2065–71.PubMedCrossRef
103.
Mohammad HP, Smitheman KN, Kamat CD, Soong D, Federowicz KE, Van Aller GS, et al. A DNA hypomethylation signature predicts antitumor activity of LSD1 inhibitors in SCLC. Cancer Cell. 2015;28(1):57–69.PubMedCrossRef
104.
Neelamegam R, Ricq EL, Malvaez M, Patnaik D, Norton S, Carlin SM, et al. Brain-penetrant LSD1 inhibitors can block memory consolidation. ACS Chem Neurosci. 2012;3(2):120–8.PubMedCrossRef
105.
Sorna V, Theisen ER, Stephens B, Warner SL, Bearss DJ, Vankayalapati H, et al. High-throughput virtual screening identifies novel N'-(1-phenylethylidene)-benzohydrazides as potent, specific, and reversible LSD1 inhibitors. J Med Chem. 2013;56(23):9496–508.PubMedCrossRef
106.
Zheng YC, Duan YC, Ma JL, Xu RM, Zi X, Lv WL, et al. Triazole-dithiocarbamate based selective lysine specific demethylase 1 (LSD1) inactivators inhibit gastric cancer cell growth, invasion, and migration. J Med Chem. 2013;56(21):8543–60.PubMedCrossRef
107.
Fiskus W, Sharma S, Shah B, Portier BP, Devaraj SG, Liu K, et al. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia. 2014;28(11):2155–64.PubMedPubMedCentralCrossRef
108.
Prusevich P, Kalin JH, Ming SA, Basso M, Givens J, Li X, et al. A Selective Phenelzine Analogue Inhibitor of Histone Demethylase LSD1. ACS Chem Biol. 2014;9(6):1284–93.PubMedPubMedCentralCrossRef
109.
Huang Y, Greene E, Murray Stewart T, Goodwin AC, Baylin SB, Woster PM, et al. Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes. Proc Natl Acad Sci U S A. 2007;104(19):8023–8.PubMedPubMedCentralCrossRef
110.
Sharma SK, Wu Y, Steinbergs N, Crowley ML, Hanson AS, Casero RA, et al. (Bis)urea and (bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators. J Med Chem. 2010;53(14):5197–212.PubMedPubMedCentralCrossRef
111.
Feng Z, Yao Y, Zhou C, Chen F, Wu F, Wei L, et al. Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia. J Hematol Oncol. 2016;9(1):24.PubMedPubMedCentralCrossRef
112.
Wu F, Zhou C, Yao Y, Wei L, Feng Z, Deng L, et al. 3-(Piperidin-4-ylmethoxy)pyridine Containing Compounds Are Potent Inhibitors of Lysine Specific Demethylase 1. J Med Chem. 2016;59(1):253–63.PubMedCrossRef
113.
114.
Dou Y, Milne TA, Tackett AJ, Smith ER, Fukuda A, Wysocka J, et al. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell. 2005;121(6):873–85.PubMedCrossRef
115.
Cao F, Chen Y, Cierpicki T, Liu Y, Basrur V, Lei M, et al. An Ash2L/RbBP5 heterodimer stimulates the MLL1 methyltransferase activity through coordinated substrate interactions with the MLL1 SET domain. PLoS One. 2010;5(11):e14102.PubMedPubMedCentralCrossRef
116.
Cao F, Townsend EC, Karatas H, Xu J, Li L, Lee S, et al. Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia. Mol Cell. 2014;53(2):247–61.PubMedPubMedCentralCrossRef
117.
Karatas H, Townsend EC, Cao F, Chen Y, Bernard D, Liu L, et al. High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction. J Am Chem Soc. 2013;135(2):669–82.PubMedCrossRef
118.
Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002;298(5595):1039–43.PubMedCrossRef
119.
Muller J, Hart CM, Francis NJ, Vargas ML, Sengupta A, Wild B, et al. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell. 2002;111(2):197–208.PubMedCrossRef
120.
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(22):2893–905.PubMedPubMedCentralCrossRef
121.
122.
Francis NJ, Kingston RE. Mechanisms of transcriptional memory. Nat Rev Mol Cell Biol. 2001;2(6):409–21.PubMedCrossRef
123.
Simon JA, Tamkun JW. Programming off and on states in chromatin: mechanisms of Polycomb and trithorax group complexes. Curr Opin Genet Dev. 2002;12(2):210–8.PubMedCrossRef
124.
Cao R, Zhang Y. SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol Cell. 2004;15(1):57–67.PubMedCrossRef
125.
Pasini D, Bracken AP, Jensen MR, Lazzerini Denchi E, Helin K. Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J. 2004;23(20):4061–71.PubMedPubMedCentralCrossRef
126.
Crea F, Paolicchi E, Marquez VE, Danesi R. Polycomb genes and cancer: time for clinical application? Crit Rev Oncol Hematol. 2012;83(2):184–93.PubMedCrossRef
127.
Squazzo SL, O'Geen H, Komashko VM, Krig SR, Jin VX, Jang SW, et al. Suz12 binds to silenced regions of the genome in a cell-type-specific manner. Genome Res. 2006;16(7):890–900.PubMedPubMedCentralCrossRef
128.
Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006;439(7078):871–4.PubMedCrossRef
129.
O'Carroll D, Erhardt S, Pagani M, Barton SC, Surani MA, Jenuwein T. The polycomb-group gene Ezh2 is required for early mouse development. Mol Cell Biol. 2001;21(13):4330–6.PubMedPubMedCentralCrossRef
130.
Wang X, Zhao H, Lv L, Bao L, Han S. Prognostic Significance of EZH2 Expression in Non-Small Cell Lung Cancer: A Meta-analysis. Scientific reports. 2016;6:19239.PubMedPubMedCentralCrossRef
131.
Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, 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(20):11606–11.PubMedPubMedCentralCrossRef
132.
Simon JA, Lange CA. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res. 2008;647(1–2):21–9.PubMedCrossRef
133.
Li Z, Wang Y, Qiu J, Li Q, Yuan C, Zhang W, et al. The polycomb group protein EZH2 is a novel therapeutic target in tongue cancer. Oncotarget. 2013;4(12):2532–49.PubMedPubMedCentralCrossRef
134.
Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002;419(6907):624–9.PubMedCrossRef
135.
Weikert S, Christoph F, Kollermann J, Muller M, Schrader M, Miller K, et al. Expression levels of the EZH2 polycomb transcriptional repressor correlate with aggressiveness and invasive potential of bladder carcinomas. Int J Mol Med. 2005;16(2):349–53.PubMed
136.
Shi J, Wang E, Zuber J, Rappaport A, Taylor M, Johns C, et al. The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;Nras(G12D) acute myeloid leukemia. Oncogene. 2013;32(7):930–8.PubMedCrossRef
137.
Suva ML, Riggi N, Janiszewska M, Radovanovic I, Provero P, Stehle JC, et al. EZH2 is essential for glioblastoma cancer stem cell maintenance. Cancer Res. 2009;69(24):9211–8.PubMedCrossRef
138.
Knutson SK, Kawano S, Minoshima Y, Warholic NM, Huang KC, Xiao Y, 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(4):842–54.PubMedCrossRef
139.
McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012;492(7427):108–12.PubMedCrossRef
140.
Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A. 2012;109(10):3879–84.PubMedPubMedCentralCrossRef
141.
Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42(2):181–5.PubMedPubMedCentralCrossRef
142.
Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;476(7360):298–303.PubMedPubMedCentralCrossRef
143.
Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM, Richon VM, et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci U S A. 2010;107(49):20980–5.PubMedPubMedCentralCrossRef
144.
McCabe MT, Graves AP, Ganji G, Diaz E, Halsey WS, Jiang Y, et al. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci U S A. 2012;109(8):2989–94.PubMedPubMedCentralCrossRef
145.
Wigle TJ, Knutson SK, Jin L, Kuntz KW, Pollock RM, Richon VM, et al. The Y641C mutation of EZH2 alters substrate specificity for histone H3 lysine 27 methylation states. FEBS Lett. 2011;585(19):3011–4.PubMedCrossRef
146.
Bradley WD, Arora S, Busby J, Balasubramanian S, Gehling VS, Nasveschuk CG, et al. EZH2 inhibitor efficacy in non-Hodgkin's lymphoma does not require suppression of H3K27 monomethylation. Chemistry & biology. 2014;21(11):1463–75.CrossRef
147.
Garapaty-Rao S, Nasveschuk C, Gagnon A, Chan EY, Sandy P, Busby J, et al. Identification of EZH2 and EZH1 small molecule inhibitors with selective impact on diffuse large B cell lymphoma cell growth. Chemistry & biology. 2013;20(11):1329–39.CrossRef
148.
Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol. 2012;8(11):890–6.PubMed
149.
Konze KD, Ma A, Li F, Barsyte-Lovejoy D, Parton T, Macnevin CJ, et al. An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1. ACS Chem Biol. 2013;8(6):1324–34.PubMedPubMedCentralCrossRef
150.
Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E, et al. Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J Biol Chem. 2004;279(32):33946–57.PubMedCrossRef
151.
Haselbeck RJ, McAlister-Henn L. Function and expression of yeast mitochondrial NAD- and NADP-specific isocitrate dehydrogenases. J Biol Chem. 1993;268(16):12116–22.PubMed
152.
Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321(5897):1807–12.PubMedPubMedCentralCrossRef
153.
Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Christians A, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol. 2009;118(4):469–74.PubMedCrossRef
154.
155.
Bleeker FE, Lamba S, Leenstra S, Troost D, Hulsebos T, Vandertop WP, et al. IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat. 2009;30(1):7–11.PubMedCrossRef
156.
Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008;116(6):597–602.PubMedCrossRef
157.
Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG, et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 2010;207(2):339–44.PubMedPubMedCentralCrossRef
158.
Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 2011;224(3):334–43.PubMedCrossRef
159.
Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553–67.PubMedPubMedCentralCrossRef
160.
Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrozek K, Margeson D, et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(14):2348–55.CrossRef
161.
Dang L, Jin S, Su SM. IDH mutations in glioma and acute myeloid leukemia. Trends Mol Med. 2010;16(9):387–97.PubMedCrossRef
162.
Yen KE, Bittinger MA, Su SM, Fantin VR. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene. 2010;29(49):6409–17.PubMedCrossRef
163.
Watanabe T, Nobusawa S, Kleihues P, Ohgaki H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol. 2009;174(4):1149–53.PubMedPubMedCentralCrossRef
164.
Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739–44.PubMedPubMedCentralCrossRef
165.
Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 2009;324(5924):261–5.PubMedPubMedCentralCrossRef
166.
Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17(3):225–34.PubMedPubMedCentralCrossRef
167.
Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17–30.PubMedPubMedCentralCrossRef
168.
Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;483(7390):479–83.PubMedPubMedCentralCrossRef
169.
Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17(5):510–22.PubMedPubMedCentralCrossRef
170.
Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;483(7390):474–8.PubMedPubMedCentralCrossRef
171.
Popovici-Muller J, Saunders JO, Salituro FG, Travins JM, Yan S, Zhao F, et al. Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumor 2-HG in Vivo. ACS Med Chem Lett. 2012;3(10):850–5.PubMedPubMedCentralCrossRef
172.
Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science. 2013;340(6132):626–30.PubMedPubMedCentralCrossRef
173.
Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science. 2013;340(6132):622–6.PubMedCrossRef
174.
Zheng B, Yao Y, Liu Z, Deng L, Anglin JL, Jiang H, et al. Crystallographic Investigation and Selective Inhibition of Mutant Isocitrate Dehydrogenase. ACS Med Chem Lett. 2013;4(6):542–6.PubMedPubMedCentralCrossRef
175.
Liu Z, Yao Y, Kogiso M, Zheng B, Deng L, Qiu JJ, et al. Inhibition of cancer-associated mutant isocitrate dehydrogenases: synthesis, structure-activity relationship, and selective antitumor activity. J Med Chem. 2014;57(20):8307–18.PubMedPubMedCentralCrossRef
176.
Wu F, Jiang H, Zheng B, Kogiso M, Yao Y, Zhou C, et al. Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds. J Med Chem. 2015;58(17):6899–908.PubMedCrossRef
177.
Deng G, Shen J, Yin M, McManus J, Mathieu M, Gee P, et al. Selective inhibition of mutant isocitrate dehydrogenase 1 (IDH1) via disruption of a metal binding network by an allosteric small molecule. J Biol Chem. 2015;290(2):762–74.PubMedCrossRef
178.
Baldwin RM, Morettin A, Cote J. Role of PRMTs in cancer: Could minor isoforms be leaving a mark? World J Biol Chem. 2014;5(2):115–29.PubMedPubMedCentral
179.
Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M, et al. G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 2002;16(14):1779–91.PubMedPubMedCentralCrossRef
180.
Huang J, Dorsey J, Chuikov S, Perez-Burgos L, Zhang X, Jenuwein T, et al. G9a and Glp methylate lysine 373 in the tumor suppressor p53. J Biol Chem. 2010;285(13):9636–41.PubMedPubMedCentralCrossRef
181.
Kondo Y, Shen L, Ahmed S, Boumber Y, Sekido Y, Haddad BR, et al. Downregulation of histone H3 lysine 9 methyltransferase G9a induces centrosome disruption and chromosome instability in cancer cells. PLoS One. 2008;3(4):e2037.PubMedPubMedCentralCrossRef
182.
Kondo Y, Shen L, Suzuki S, Kurokawa T, Masuko K, Tanaka Y, et al. Alterations of DNA methylation and histone modifications contribute to gene silencing in hepatocellular carcinomas. Hepatol Res. 2007;37(11):974–83.PubMedCrossRef
183.
Kubicek S, O'Sullivan RJ, August EM, Hickey ER, Zhang Q, Teodoro ML, et al. Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol Cell. 2007;25(3):473–81.PubMedCrossRef
184.
Vedadi M, Barsyte-Lovejoy D, Liu F, Rival-Gervier S, Allali-Hassani A, Labrie V, et al. A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nat Chem Biol. 2011;7(8):566–74.PubMedPubMedCentralCrossRef
185.
Sweis RF, Pliushchev M, Brown PJ, Guo J, Li F, Maag D, et al. Discovery and development of potent and selective inhibitors of histone methyltransferase g9a. ACS Med Chem Lett. 2014;5(2):205–9.PubMedPubMedCentralCrossRef
186.
Kalari KR, Hebbring SJ, Chai HS, Li L, Kocher JP, Wang L, et al. Copy number variation and cytidine analogue cytotoxicity: a genome-wide association approach. BMC Genomics. 2010;11:357.PubMedPubMedCentralCrossRef
187.
Komatsu S, Imoto I, Tsuda H, Kozaki KI, Muramatsu T, Shimada Y, et al. Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma. Carcinogenesis. 2009;30(7):1139–46.PubMedCrossRef
188.
Ferguson AD, Larsen NA, Howard T, Pollard H, Green I, Grande C, et al. Structural basis of substrate methylation and inhibition of SMYD2. Structure. 2011;19(9):1262–73.PubMedCrossRef
189.
Nguyen H, Allali-Hassani A, Antonysamy S, Chang S, Chen LH, Curtis C, et al. LLY-507, a cell-active, potent, and selective inhibitor of protein-lysine methyltransferase SMYD2. J Biol Chem. 2015;290(22):13641–53.PubMedPubMedCentralCrossRef
190.
Sack JS, Thieffine S, Bandiera T, Fasolini M, Duke GJ, Jayaraman L, et al. Structural basis for CARM1 inhibition by indole and pyrazole inhibitors. The Biochemical journal. 2011;436(2):331–9.PubMedCrossRef
191.
Kaniskan HU, Szewczyk MM, Yu Z, Eram MS, Yang X, Schmidt K, et al. A potent, selective and cell-active allosteric inhibitor of protein arginine methyltransferase 3 (PRMT3). Angew Chem Int Ed Engl. 2015;54(17):5166–70.PubMedPubMedCentralCrossRef
192.
Mitchell LH, Drew AE, Ribich SA, Rioux N, Swinger KK, Jacques SL, et al. Aryl pyrazoles as potent inhibitors of arginine methyltransferases: identification of the first PRMT6 tool compound. ACS Med Chem Lett. 2015;6(6):655–9.PubMedPubMedCentralCrossRef
193.
Eram MS, Shen Y, Szewczyk MM, Wu H, Senisterra G, Li F, et al. A potent, selective, and cell-active inhibitor of human type I protein arginine methyltransferases. ACS Chem Biol. 2016;11(3):772–81.PubMedCrossRef
194.
Chan-Penebre E, Kuplast KG, Majer CR, Boriack-Sjodin PA, Wigle TJ, Johnston LD, et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol. 2015;11(6):432–7.PubMedCrossRef
195.
Kruidenier L, Chung CW, Cheng Z, Liddle J, Che K, Joberty G, et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature. 2012;488(7411):404–8.PubMedPubMedCentralCrossRef
196.
Cui Y, Tong H, Du X, Li B, Gale RP, Qin T, et al. Impact of TET2, SRSF2, ASXL1 and SETBP1 mutations on survival of patients with chronic myelomonocytic leukemia. Exp Hematol Oncol. 2015;4:14.PubMedPubMedCentralCrossRef
197.
Guillaumet-Adkins A, Richter J, Odero MD, Sandoval J, Agirre X, Catala A, et al. Hypermethylation of the alternative AWT1 promoter in hematological malignancies is a highly specific marker for acute myeloid leukemias despite high expression levels. J Hematol Oncol. 2014;7:4.PubMedPubMedCentralCrossRef
198.
Hajkova H, Fritz MH, Haskovec C, Schwarz J, Salek C, Markova J, et al. CBFB-MYH11 hypomethylation signature and PBX3 differential methylation revealed by targeted bisulfite sequencing in patients with acute myeloid leukemia. J Hematol Oncol. 2014;7:66.PubMedPubMedCentralCrossRef
199.
200.
Cang S, Ma Y, Chiao JW, Liu D. Phenethyl isothiocyanate and paclitaxel synergistically enhanced apoptosis and alpha-tubulin hyperacetylation in breast cancer cells. Exp Hematol Oncol. 2014;3(1):5.PubMedPubMedCentralCrossRef
Metadata
Title
Targeting histone methylation for cancer therapy: enzymes, inhibitors, biological activity and perspectives
Authors
Yongcheng Song
Fangrui Wu
Jingyu Wu
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-016-0279-9

Other articles of this Issue 1/2016

Journal of Hematology & Oncology 1/2016 Go to the issue

Research

Azacitidine front-line in 339 patients with myelodysplastic syndromes and acute myeloid leukaemia: comparison of French-American-British and World Health Organization classifications

Research

Synergism between the mTOR inhibitor rapamycin and FAK down-regulation in the treatment of acute lymphoblastic leukemia

Rapid communication

Oligoclonal expansion of TCR Vδ T cells may be a potential immune biomarker for clinical outcome of acute myeloid leukemia

Case report

Programmed cell death-1 blockade in recurrent disseminated Ewing sarcoma

Research

PEG-aspargase and DEP regimen combination therapy for refractory Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis

Letter to the Editor

High IKZF1/3 protein expression is a favorable prognostic factor for survival of relapsed/refractory multiple myeloma patients treated with lenalidomide
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