@article{e11ca81e41d34a1a87b4dde56230f2ce,
title = "Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy",
abstract = "The dynamic evolution of chromatin state patterns during metastasis, their relationship with bona fide genetic drivers, and their therapeutic vulnerabilities are not completely understood. Combinatorial chromatin state profiling of 46 melanoma samples reveals an association of NRAS mutants with bivalent histone H3 lysine 27 trimethylation (H3K27me3) and Polycomb repressive complex 2. Reprogramming of bivalent domains during metastasis occurs on master transcription factors of a mesenchymal phenotype, including ZEB1, TWIST1, and CDH1. Resolution of bivalency using pharmacological inhibition of EZH2 decreases invasive capacity of melanoma cells and markedly reduces tumor burden in vivo, specifically in NRAS mutants. Coincident with bivalent reprogramming, the increased expression of pro-metastatic and melanocyte-specific cell-identity genes is associated with exceptionally wide H3K4me3 domains, suggesting a role for this epigenetic element. Overall, we demonstrate that reprogramming of bivalent and broad domains represents key epigenetic alterations in metastatic melanoma and that EZH2 plus MEK inhibition may provide a promising therapeutic strategy for NRAS mutant melanoma patients.",
keywords = "Polycomb repressive complex 2, bivalent, broad domains, chromatin, epigenetics, melanoma, melanoma therapeutics, metastasis",
author = "Terranova, {Christopher J.} and Ming Tang and Mayinuer Maitituoheti and Raman, {Ayush T.} and Ghosh, {Archit K.} and Jonathan Schulz and Amin, {Samir B.} and Elias Orouji and Katarzyna Tomczak and Sharmistha Sarkar and Junna Oba and Caitlin Creasy and Wu, {Chang Jiun} and Samia Khan and Rossana Lazcano and Khalida Wani and Anand Singh and Praveen Barrodia and Dongyu Zhao and Kaifu Chen and Haydu, {Lauren E.} and Wang, {Wei Lien} and Lazar, {Alexander J.} and Woodman, {Scott E.} and Chantale Bernatchez and Kunal Rai",
note = "Funding Information: We are grateful to Kadir C. Akdemir, Yonathan Lissanu Deribe, Anand Singh, Scott Callahan, Veena Kochat, Sharon Landers, Angela Bhalla, and Keila Torres for helpful discussions and proofreading the manuscript. The work described in this article was supported by grants from the National Institutes of Health ( CA160578 to K.R.; CA016672 to SMF Core), Center for Cancer Epigenetics at MDACC (to C.J.T. and K.R.), and MD Anderson Cancer Center (start-up funds to K.R.). Short tandem repeat (STR) DNA fingerprinting was done by the UTMDACC CCSG-funded Characterized Cell Line Core, NCI CA016672 . The molecular characterization of the short-term culture tumor lines was supported by generous philanthropic contributions to The University of Texas MD Anderson Moon Shots Program. Funding Information: We are grateful to Kadir C. Akdemir, Yonathan Lissanu Deribe, Anand Singh, Scott Callahan, Veena Kochat, Sharon Landers, Angela Bhalla, and Keila Torres for helpful discussions and proofreading the manuscript. The work described in this article was supported by grants from the National Institutes of Health (CA160578 to K.R.; CA016672 to SMF Core), Center for Cancer Epigenetics at MDACC (to C.J.T. and K.R.), and MD Anderson Cancer Center (start-up funds to K.R.). Short tandem repeat (STR) DNA fingerprinting was done by the UTMDACC CCSG-funded Characterized Cell Line Core, NCI CA016672. The molecular characterization of the short-term culture tumor lines was supported by generous philanthropic contributions to The University of Texas MD Anderson Moon Shots Program. C.J.T. and K.R. conceptualized and designed the study. C.J.T. and M.M. generated ChIP-seq data. C.J.T. M.T. M.M. and S.A. processed ChIP-seq data. C.J.T. M.T. A.R. and J.S. performed data analysis for ChIP-seq. C.J.T. M.T. and A.T.R. processed and performed data analysis for RNA-seq. K.R. performed in vivo experiments. C.J.T. performed proliferation and invasion assays. M.M. quantified proliferation assays. K.R. and C.J.T. quantified invasion assays. A.K.G. and C.J.T. performed and quantified western blotting analysis. C.J.T. generated CRISPR-Cas9 cell lines. C.J.T. performed dose-dependent qRT-PCR assays. M.M. performed IHC for in vivo mouse tissues. P.B. performed IHC imaging for in vivo mouse tissues. S.K. R.L. and K.W. performed IHC for patient TMAs. J.O. C.C. C.J.W. C.B. and S.E.W. generated and characterized the STCs. E.O. A.S. S.S. K.T. D.Z. and K.C. provided intellectual input. C.J.T. and K.R. wrote and prepared the manuscript. All authors read and approved the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = jul,
day = "20",
doi = "10.1016/j.celrep.2021.109410",
language = "English",
volume = "36",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}