1. Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy.
- Author
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Terranova CJ, Tang M, Maitituoheti M, Raman AT, Ghosh AK, Schulz J, Amin SB, Orouji E, Tomczak K, Sarkar S, Oba J, Creasy C, Wu CJ, Khan S, Lazcano R, Wani K, Singh A, Barrodia P, Zhao D, Chen K, Haydu LE, Wang WL, Lazar AJ, Woodman SE, Bernatchez C, and Rai K
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation, Enhancer of Zeste Homolog 2 Protein metabolism, Female, GTP Phosphohydrolases metabolism, Histones metabolism, Humans, Melanocytes metabolism, Membrane Proteins metabolism, Mesoderm metabolism, Mice, Nude, Mitogen-Activated Protein Kinase Kinases metabolism, Neoplasm Metastasis, Polycomb Repressive Complex 2 metabolism, Transcription, Genetic, Tumor Burden, Mice, Chromatin metabolism, GTP Phosphohydrolases genetics, Melanoma genetics, Membrane Proteins genetics, Mutation genetics, Polycomb Repressive Complex 2 antagonists & inhibitors
- 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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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