Epigenome Reprogramming Through H3K27 and H3K4 Trimethylation as a Resistance Mechanism to DNA Methylation Inhibition in BRAFV600E-Mutated Colorectal Cancer

被引：4

作者：

Lee, Hey Min ^{[1
]}

Saw, Ajay Kumar ^{[2
]}

Morris, Van K. ^{[1
]}

Napolitano, Stefania ^{[1
]}

Bristow, Christopher ^{[3
]}

Srinivasan, Sanjana ^{[3
]}

Peoples, Micheal ^{[3
]}

Sorokin, Alexey ^{[1
]}

Marie, Preeti Kanikarla ^{[1
]}

Schulz, Jonathan ^{[2
]}

Singh, Anand K. ^{[2
]}

Terranova, Christopher ^{[2
]}

Coker, Oluwadara ^{[1
]}

Jain, Abhinav ^{[4
]}

Kopetz, Scott ^{[1
]}

Rai, Kunal ^{[2
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, 1515 Holcombe Blvd,Unit 0426, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, South Campus Res Bldg 4 4SCR6 1047,1901 East Rd,Un, Houston, TX 77054 USA

[3] Univ Texas MD Anderson Canc Ctr, TRACT Platform, Houston, TX USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Epigenet & Mol Carcinogenesis, Houston, TX USA

来源：

CLINICAL CANCER RESEARCH | 2024年 / 30卷 / 22期

关键词：

MICROSATELLITE INSTABILITY; TUMOR-SUPPRESSOR; BRAF MUTATION; PHENOTYPE; GENOME; GENES; EPIGENETICS; EXPRESSION; CHROMATIN; PATTERNS;

D O I：

10.1158/1078-0432.CCR-24-1166

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: BRAFV600E-mutated colorectal cancer exhibits a strong correlation with DNA hypermethylation, suggesting that this subgroup of tumors presents unique epigenomic phenotypes. Nonetheless, 5-azacitidine, which inhibits DNA methyltransferase activity, is not efficacious in BRAFV600E colorectal cancer in vivo.Experimental Design: We randomized and treated mice implanted with patient-derived tumor xenografts harboring BRAFV600E mutation with control, 5-azacitidine, vemurafenib (BRAF inhibitor), or the combination. Comprehensive epigenomic profiling was conducted on control and 5-azacitidine-treated tumor samples, including DNA methylation, histone modifications, chromatin accessibility, and gene expression. Combinations of epigenetic agents were explored in preclinical BRAFV600E colorectal cancer models.Results: A profound reduction of DNA methylation levels upon 5-azacitidine treatment was confirmed, however, transcriptional repression was not relieved. This study unbiasedly explored the adaptive engagement of other epigenomic modifications upon 5-azacitidine treatment. A loss of histone acetylation and a gain of histone methylations, including H3K27 and H3K4 trimethylation, were observed around these hypomethylated regions, suggesting the involvement of polycomb repressive complex (PRC) activity around the genome with loss of DNA methylation, therefore maintaining the repression of key tumor-suppressor genes. Combined inhibition of PRC activity through EZH2 inhibition with 5-azacitidine treatment additively improved efficacies in BRAFV600E colorectal cancer cells.Conclusions: In conclusion, DNA hypomethylation by 5-azacitidine exhibits a close association with H3K27me3 and PRC activity in BRAFV600E colorectal cancer, and simultaneous blockade of DNA methyltransferase and EZH2 holds promise as a potential therapeutic strategy for patients with BRAFV600E-mutated colorectal cancer.

引用

页码：5166 / 5179

页数：14

共 55 条

[1] Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat; a phase 2 consortium/stand Up 2 cancer study [J].

Azad, Nilofer S. ;

el-Khoueiry, Anthony ;

Yin, Jun ;

Oberg, Ann L. ;

Flynn, Patrick ;

Adkins, Douglas ;

Sharma, Anup ;

Weisenberger, Daniel J. ;

Brown, Thomas ;

Medvari, Prakriti ;

Jones, Peter A. ;

Easwaran, Hariharan ;

Kamel, Ihab ;

Bahary, Nathan ;

Kim, George ;

Picus, Joel ;

Pitot, Henry C. ;

Erlichman, Charles ;

Donehower, Ross ;

Shen, Hui ;

Laird, Peter W. ;

Piekarz, Richard ;

Baylin, Stephen ;

Ahuja, Nita .

ONCOTARGET, 2017, 8 (21) :35326-35338

[2] Epigenetically regulated Fibronectin leucine rich transmembrane protein 2 (FLRT2) shows tumor suppressor activity in breast cancer cells [J].

Bae, Hansol ;

Kim, Byungtak ;

Lee, Hyunkyung ;

Lee, Seungyeon ;

Kang, Han-Sung ;

Kim, Sun Jung .

SCIENTIFIC REPORTS, 2017, 7

[3] A study of using epigenetic modulators to enhance response to pembrolizumab (MK-3475) in microsatellite stable advanced colorectal cancer [J].

Baretti, Marina ;

Murphy, Adrian. G. G. ;

Zahurak, Marianna ;

Gianino, Nicole ;

Parkinson, Rose ;

Walker, Rosalind ;

Lopez-Vidal, Tamara. Y. Y. ;

Zheng, Lei ;

Rosner, Gary ;

Ahuja, Nita ;

Kurt, Schalper ;

Azad, Nilofer. S. S. .

CLINICAL EPIGENETICS, 2023, 15 (01)

[4] Epigenetic Determinants of Cancer [J].

Baylin, Stephen B. ;

Jones, Peter A. .

COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY, 2016, 8 (09)

[5] Sequential ChIP-bisulfite sequencing enables direct genome-scale investigation of chromatin and DNA methylation cross-talk [J].

Brinkman, Arie B. ;

Gu, Hongcang ;

Bartels, Stefanie J. J. ;

Zhang, Yingying ;

Matarese, Filomena ;

Simmer, Femke ;

Marks, Hendrik ;

Bock, Christoph ;

Gnirke, Andreas ;

Meissner, Alexander ;

Stunnenberg, Hendrik G. .

GENOME RESEARCH, 2012, 22 (06) :1128-1138

[6] Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer [J].

Cameron, EE ;

Bachman, KE ;

Myöhänen, S ;

Herman, JG ;

Baylin, SB .

NATURE GENETICS, 1999, 21 (01) :103-107

[7] Comprehensive molecular characterization of human colon and rectal cancer [J].

Muzny, Donna M. ;

Bainbridge, Matthew N. ;

Chang, Kyle ;

Dinh, Huyen H. ;

Drummond, Jennifer A. ;

Fowler, Gerald ;

Kovar, Christie L. ;

Lewis, Lora R. ;

Morgan, Margaret B. ;

Newsham, Irene F. ;

Reid, Jeffrey G. ;

Santibanez, Jireh ;

Shinbrot, Eve ;

Trevino, Lisa R. ;

Wu, Yuan-Qing ;

Wang, Min ;

Gunaratne, Preethi ;

Donehower, Lawrence A. ;

Creighton, Chad J. ;

Wheeler, David A. ;

Gibbs, Richard A. ;

Lawrence, Michael S. ;

Voet, Douglas ;

Jing, Rui ;

Cibulskis, Kristian ;

Sivachenko, Andrey ;

Stojanov, Petar ;

McKenna, Aaron ;

Lander, Eric S. ;

Gabriel, Stacey ;

Getz, Gad ;

Ding, Li ;

Fulton, Robert S. ;

Koboldt, Daniel C. ;

Wylie, Todd ;

Walker, Jason ;

Dooling, David J. ;

Fulton, Lucinda ;

Delehaunty, Kim D. ;

Fronick, Catrina C. ;

Demeter, Ryan ;

Mardis, Elaine R. ;

Wilson, Richard K. ;

Chu, Andy ;

Chun, Hye-Jung E. ;

Mungall, Andrew J. ;

Pleasance, Erin ;

Robertson, A. Gordon ;

Stoll, Dominik ;

Balasundaram, Miruna .

NATURE, 2012, 487 (7407) :330-337

[8] Linking DNA methylation and histone modification: patterns and paradigms [J].

Cedar, Howard ;

Bergman, Yehudit .

NATURE REVIEWS GENETICS, 2009, 10 (05) :295-304

[9] Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses [J].

Chiappinelli, Katherine B. ;

Strissel, Pamela L. ;

Desrichard, Alexis ;

Li, Huili ;

Henke, Christine ;

Akman, Benjamin ;

Hein, Alexander ;

Rote, Neal S. ;

Cope, Leslie M. ;

Snyder, Alexandra ;

Makarov, Vladimir ;

Buhu, Sadna ;

Slamon, Dennis J. ;

Wolchok, Jedd D. ;

Pardoll, Drew M. ;

Beckmann, Matthias W. ;

Zahnow, Cynthia A. ;

Mergoub, Taha ;

Chan, Timothy A. ;

Baylin, Stephen B. ;

Strick, Reiner .

CELL, 2015, 162 (05) :974-986

[10]

Corces MR, 2017, NAT METHODS, V14, P959, DOI [10.1038/NMETH.4396, 10.1038/nmeth.4396]

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