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BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

Contrasting roles of H3K4me3 and H3K9me3 in regulation of apoptosis and gemcitabine resistance in human pancreatic cancer cells

Authors: Chunwan Lu, Dafeng Yang, Maria E. Sabbatini, Aaron H. Colby, Mark W. Grinstaff, Nicholas H. Oberlies, Cedric Pearce, Kebin Liu

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

Pancreas ductal adenocarcinoma (PDAC) has the most dismal prognosis among all human cancers since it is highly resistant to chemotherapy, radiotherapy and immunotherapy. The anticipated consequence of all therapies is induction of tumor apoptosis. The highly resistance nature of PDACs to all therapies suggests that the intrinsic tumor cell factors, likely the deregulated apoptosis pathway, are key mechanisms underlying PDAC non-response to these therapies, rather than the therapeutic agents themselves. The aim of this study is to test the hypothesis that epigenetic dysregulation of apoptosis mediators underlies PDAC resistance to gemcitabine, the standard chemotherapy for human PDAC.

Methods

PDAC cells were analyzed for apoptosis sensitivity in the presence of a selective epigenetic inhibitor. The epigenetic regulation of apoptosis regulators was determined by Western Blotting and quantitative PCR. The specific epigenetic modification of apoptosis regulator promoter chromatin was determined by chromatin immunoprecipitation in PDAC cells.

Results

Inhibition of histone methyltransferase (HMTase) by a selective HMTase inhibitor, verticillin A, significantly increased human PDAC cell sensitivity to gemcitabine-induced growth suppression. Verticillin A treatment decreased FLIP, Mcl-1, Bcl-x and increased Bak, Bax and Bim protein level in the tumor cells, resulting in activation of caspases, elevated cytochrome C release and increased apoptosis as determined by upregulated PARP cleavage in tumor cells. Analysis of human PDAC specimens indicated that the expression levels of anti-apoptotic mediators Bcl-x, Mcl-1, and FLIP were significantly higher, whereas the expression levels of pro-apoptotic mediators Bim, Bak and Bax were dramatically lower in human PDAC tissues as compared to normal pancreas. Verticillin A downregulated H3K4me3 levels at the BCL2L1, CFLAR and MCL-1 promoter to decrease Bcl-x, FLIP and Mcl-1 expression level, and inhibited H3K9me3 levels at the BAK1, BAX and BCL2L11 promoter to upregulate Bak, Bax and Bim expression level.

Conclusion

We determined that PDAC cells use H3K4me3 to activate Bcl-x, FLIP and Mcl-1, and H3K9me3 to silence Bak, Bax and Bim to acquire an apoptosis-resistant phenotype. Therefore, selective inhibition of H3K4me3 and H3K9me3 is potentially an effective approach to overcome PDAC cells resistance to gemcitabine.
Literature
1.
Muniraj T, Jamidar PA, Aslanian HR. Pancreatic cancer: a comprehensive review and update. Dis Mon. 2013;59(11):368–402.CrossRefPubMed
2.
Kumar R, Herman JM, Wolfgang CL, Zheng L. Multidisciplinary management of pancreatic cancer. Surg Oncol Clin N Am. 2013;22(2):265–87.CrossRefPubMed
3.
Rucki AA, Foley K, Zhang P, Xiao Q, Kleponis J, Wu AA, Sharma R, Mo G, Liu A, Van Eyk J, et al. Heterogeneous stromal signaling within the tumor microenvironment controls the metastasis of pancreatic cancer. Cancer Res. 2017;77(1):41–52.CrossRefPubMed
4.
Delitto D, Delitto AE, BB DV, Pham K, Han S, Hartlage ER, Newby BN, Gerber MH, Behrns KE, Moldawer LL, et al. Human pancreatic cancer cells induce a MyD88-dependent stromal response to promote a tumor-tolerant immune microenvironment. Cancer Res. 2017;77(3):672–83.CrossRefPubMed
5.
Binenbaum Y, Na’ara S, Gil Z. Gemcitabine resistance in pancreatic ductal adenocarcinoma. Drug Resist Updat. 2015;23:55–68.CrossRefPubMed
6.
Lu C, Paschall AV, Shi H, Savage N, Waller JL, Sabbatini ME, Oberlies NH, Pearce C, Liu K. The MLL1-H3K4me3 axis-mediated PD-L1 expression and pancreatic cancer immune evasion. J Natl Cancer Inst. 2017;109(6):djw283.
7.
Lu C, Talukder A, Savage NM, Singh N, Liu K. JAK-STAT-mediated chronic inflammation impairs cytotoxic T lymphocyte activation to decrease anti-PD-1 immunotherapy efficacy in pancreatic cancer. Oncoimmunology. 2017;6(3):e1291106.CrossRefPubMed
8.
Delitto D, Black BS, Sorenson HL, Knowlton AE, Thomas RM, Sarosi GA, Moldawer LL, Behrns KE, Liu C, George TJ, et al. The inflammatory milieu within the pancreatic cancer microenvironment correlates with clinicopathologic parameters, chemoresistance and survival. BMC Cancer. 2015;15:783.CrossRefPubMedPubMedCentral
9.
Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, et al. Nivolumab versus Docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123–35.CrossRefPubMedPubMedCentral
10.
Villadolid J, Amin A. Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. Transl Lung Cancer Res. 2015;4(5):560–75.PubMedPubMedCentral
11.
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(26):2455–65.CrossRefPubMedPubMedCentral
12.
Foley K, Kim V, Jaffee E, Zheng L. Current progress in immunotherapy for pancreatic cancer. Cancer Lett. 2016;381(1):244–51.CrossRefPubMed
13.
Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, Sosman JA, DF MD, Powderly JD, Gettinger SN, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–7.CrossRefPubMedPubMedCentral
14.
Cappelli LC, Shah AA, Bingham CO 3rd. Immune-related adverse effects of cancer immunotherapy-implications for rheumatology. Rheum Dis Clin N Am. 2017;43(1):65–78.CrossRef
15.
Friedman CF, Clark V, Raikhel AV, Barz T, Shoushtari AN, Momtaz P, Callahan MK, Wolchok JD, Chapman PB, Hellmann MD, et al. Thinking critically about classifying adverse events: incidence of pancreatitis in patients treated with Nivolumab + Ipilimumab. J Natl Cancer Inst. 2017;109(4)
16.
Vaz AP, Deb S, Rachagani S, Dey P, Muniyan S, Lakshmanan I, Karmakar S, Smith L, Johansson S, Lele S, et al. Overexpression of PD2 leads to increased tumorigenicity and metastasis in pancreatic ductal adenocarcinoma. Oncotarget. 2016;7(3):3317–31.CrossRefPubMed
17.
Kaur S, Sharma N, Krishn SR, Lakshmanan I, Rachagani S, Baine MJ, Smith LM, Lele SM, Sasson AR, Guha S, et al. MUC4-mediated regulation of acute phase protein lipocalin 2 through HER2/AKT/NF-kappaB signaling in pancreatic cancer. Clin Cancer Res. 2014;20(3):688–700.CrossRefPubMed
18.
Rajurkar M, Dang K, Fernandez-Barrena MG, Liu X, Fernandez-Zapico ME, Lewis BC, Mao J. IKBKE is required during KRAS-induced pancreatic tumorigenesis. Cancer Res. 2017;77(2):320–9.CrossRefPubMedPubMedCentral
19.
Sivakumar S, de Santiago I, Chlon L, Markowetz F. Master regulators of Oncogenic KRAS response in pancreatic cancer: an integrative network biology analysis. PLoS Med. 2017;14(1):e1002223.CrossRefPubMedPubMedCentral
20.
21.
Melisi D, Xia Q, Paradiso G, Ling J, Moccia T, Carbone C, Budillon A, Abbruzzese JL, Chiao PJ. Modulation of pancreatic cancer chemoresistance by inhibition of TAK1. J Natl Cancer Inst. 2011;103(15):1190–204.CrossRefPubMedPubMedCentral
22.
Sherman MH, Yu RT, Tseng TW, Sousa CM, Liu S, Truitt ML, He N, Ding N, Liddle C, Atkins AR, et al. Stromal cues regulate the pancreatic cancer epigenome and metabolome. Proc Natl Acad Sci U S A. 2017;114(5):1129–34.CrossRefPubMedPubMedCentral
23.
McDonald OG, Li X, Saunders T, Tryggvadottir R, Mentch SJ, Warmoes MO, Word AE, Carrer A, Salz TH, Natsume S, et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat Genet. 2017;49:367.CrossRefPubMedPubMedCentral
24.
Manuyakorn A, Paulus R, Farrell J, Dawson NA, Tze S, Cheung-Lau G, Hines OJ, Reber H, Seligson DB, Horvath S, et al. Cellular histone modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma: results from RTOG 9704. J Clin Oncol. 2010;28(8):1358–65.CrossRefPubMedPubMedCentral
25.
Hessmann E, Johnsen SA, Siveke JT, Ellenrieder V. Epigenetic treatment of pancreatic cancer: is there a therapeutic perspective on the horizon? Gut. 2017;66(1):168–79.CrossRefPubMed
26.
27.
Spannhoff A, Hauser AT, Heinke R, Sippl W, Jung M. The emerging therapeutic potential of histone methyltransferase and demethylase inhibitors. ChemMedChem. 2009;4(10):1568–82.CrossRefPubMed
28.
Crea F, Nobili S, Paolicchi E, Perrone G, Napoli C, Landini I, Danesi R, Mini E. Epigenetics and chemoresistance in colorectal cancer: an opportunity for treatment tailoring and novel therapeutic strategies. Drug Resist Updat. 2011;14(6):280–96.CrossRefPubMed
29.
30.
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(7):598–607.CrossRefPubMedPubMedCentral
31.
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(8):566–74.CrossRefPubMedPubMedCentral
32.
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(1):53–65.CrossRefPubMedPubMedCentral
33.
Ferguson AD, Larsen NA, Howard T, Pollard H, Green I, Grande C, Cheung T, Garcia-Arenas R, Cowen S, Wu J, et al. Structural basis of substrate methylation and inhibition of SMYD2. Structure. 2011;19(9):1262–73.CrossRefPubMed
34.
Liu F, Liu Q, Yang D, Bollag WB, Robertson K, Wu P, Liu K. Verticillin A overcomes apoptosis resistance in human colon carcinoma through DNA methylation-dependent upregulation of BNIP3. Cancer Res. 2011;71(21):6807–16.CrossRefPubMedPubMedCentral
35.
Paschall AV, Yang D, Lu C, Choi JH, Li X, Liu F, Figueroa M, Oberlies NH, Pearce C, Bollag WB, et al. H3K9 Trimethylation silences Fas expression to confer colon carcinoma immune escape and 5-fluorouracil chemoresistance. J Immunol. 2015;195:1868.CrossRefPubMedPubMedCentral
36.
Lu C, Redd PS, Lee JR, Savage N, Liu K. The expression profiles and regulation of PD-L1 in tumor-induced myeloid-derived suppressor cells. OncoImmunology. 2016;5(12):1–13.CrossRef
37.
Figueroa M, Graf TN, Ayers S, Adcock AF, Kroll DJ, Yang J, Swanson SM, Munoz-Acuna U, Carcache de Blanco EJ, Agrawal R, et al. Cytotoxic epipolythiodioxopiperazine alkaloids from filamentous fungi of the Bionectriaceae. J Antibiot. 2012;65(11):559–64.CrossRefPubMedPubMedCentral
38.
Rea S, Eisenhaber F, O'Carroll D, Strahl BD, Sun ZW, Schmid M, Opravil S, Mechtler K, Ponting CP, Allis CD, et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature. 2000;406(6796):593–9.CrossRefPubMed
39.
O'Carroll D, Scherthan H, Peters AH, Opravil S, Haynes AR, Laible G, Rea S, Schmid M, Lebersorger A, Jerratsch M, et al. Isolation and characterization of Suv39h2, a second histone H3 methyltransferase gene that displays testis-specific expression. Mol Cell Biol. 2000;20(24):9423–33.CrossRefPubMedPubMedCentral
40.
Rice JC, Briggs SD, Ueberheide B, Barber CM, Shabanowitz J, Hunt DF, Shinkai Y, Allis CD. Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol Cell. 2003;12(6):1591–8.CrossRefPubMed
41.
Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W. Action of 2′,2′-difluorodeoxycytidine on DNA synthesis. Cancer Res. 1991;51(22):6110–7.PubMed
42.
Gandhi V, Legha J, Chen F, Hertel LW, Plunkett W. Excision of 2′,2′-difluorodeoxycytidine (gemcitabine) monophosphate residues from DNA. Cancer Res. 1996;56(19):4453–9.PubMed
43.
de Sousa Cavalcante L, Monteiro G. Gemcitabine: metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer. Eur J Pharmacol. 2014;741:8–16.CrossRefPubMed
44.
Ciliberto D, Staropoli N, Chiellino S, Botta C, Tassone P, Tagliaferri P. Systematic review and meta-analysis on targeted therapy in advanced pancreatic cancer. Pancreatology. 2016;16(2):249–58.CrossRefPubMed
45.
Tan N, Wong M, Nannini MA, Hong R, Lee LB, Price S, Williams K, Savy PP, Yue P, Sampath D, et al. Bcl-2/Bcl-xL inhibition increases the efficacy of MEK inhibition alone and in combination with PI3 kinase inhibition in lung and pancreatic tumor models. Mol Cancer Ther. 2013;12(6):853–64.CrossRefPubMed
46.
Huang S, Sinicrope FA. BH3 mimetic ABT-737 potentiates TRAIL-mediated apoptotic signaling by unsequestering Bim and Bak in human pancreatic cancer cells. Cancer Res. 2008;68(8):2944–51.CrossRefPubMedPubMedCentral
47.
Haag C, Stadel D, Zhou S, Bachem MG, Moller P, Debatin KM, Fulda S. Identification of c-FLIP(L) and c-FLIP(S) as critical regulators of death receptor-induced apoptosis in pancreatic cancer cells. Gut. 2011;60(2):225–37.CrossRefPubMed
48.
Stayrook KR, JH MK, Burke YD, Burke YA, Crowell PL. Induction of the apoptosis-promoting protein Bak by perillyl alcohol in pancreatic ductal adenocarcinoma relative to untransformed ductal epithelial cells. Carcinogenesis. 1997;18(8):1655–8.CrossRefPubMed
49.
Abulwerdi F, Liao C, Liu M, Azmi AS, Aboukameel A, Mady AS, Gulappa T, Cierpicki T, Owens S, Zhang T, et al. A novel small-molecule inhibitor of mcl-1 blocks pancreatic cancer growth in vitro and in vivo. Mol Cancer Ther. 2014;13(3):565–75.CrossRefPubMed
50.
Fritsch L, Robin P, Mathieu JR, Souidi M, Hinaux H, Rougeulle C, Harel-Bellan A, Ameyar-Zazoua M, Ait-Si-Ali S. A subset of the histone H3 lysine 9 methyltransferases Suv39h1, G9a, GLP, and SETDB1 participate in a multimeric complex. Mol Cell. 2010;37(1):46–56.CrossRefPubMed
51.
Tachibana M, Ueda J, Fukuda M, Takeda N, Ohta T, Iwanari H, Sakihama T, Kodama T, Hamakubo T, Shinkai Y. Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. Genes Dev. 2005;19(7):815–26.CrossRefPubMedPubMedCentral
52.
Kuo AJ, Cheung P, Chen K, Zee BM, Kioi M, Lauring J, Xi Y, Park BH, Shi X, Garcia BA, et al. NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. Mol Cell. 2011;44(4):609–20.CrossRefPubMedPubMedCentral
53.
Cao F, Townsend EC, Karatas H, Xu J, Li L, Lee S, Liu L, Chen Y, Ouillette P, Zhu J, et al. Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia. Mol Cell. 2014;53(2):247–61.CrossRefPubMedPubMedCentral
Metadata
Title
Contrasting roles of H3K4me3 and H3K9me3 in regulation of apoptosis and gemcitabine resistance in human pancreatic cancer cells
Authors
Chunwan Lu
Dafeng Yang
Maria E. Sabbatini
Aaron H. Colby
Mark W. Grinstaff
Nicholas H. Oberlies
Cedric Pearce
Kebin Liu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4061-y

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