Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy

Christopher J. Terranova, Ming Tang, Mayinuer Maitituoheti, Ayush T. Raman, Archit K. Ghosh, Jonathan Schulz, Samir B. Amin, Elias Orouji, Katarzyna Tomczak, Sharmistha Sarkar, Junna Oba, Caitlin Creasy, Chang Jiun Wu, Samia Khan, Rossana Lazcano, Khalida Wani, Anand Singh, Praveen Barrodia, Dongyu Zhao, Kaifu ChenLauren E. Haydu, Wei Lien Wang, Alexander J. Lazar, Scott E. Woodman, Chantale Bernatchez, Kunal Rai

研究成果: Article査読

4 被引用数 (Scopus)

抄録

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.

本文言語English
論文番号109410
ジャーナルCell Reports
36
3
DOI
出版ステータスPublished - 2021 7月 20
外部発表はい

ASJC Scopus subject areas

  • 生化学、遺伝学、分子生物学(全般)

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