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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number109410
JournalCell Reports
Volume36
Issue number3
DOIs
Publication statusPublished - 2021 Jul 20
Externally publishedYes

Keywords

  • bivalent
  • broad domains
  • chromatin
  • epigenetics
  • melanoma
  • melanoma therapeutics
  • metastasis
  • Polycomb repressive complex 2

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint

Dive into the research topics of 'Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy'. Together they form a unique fingerprint.

Cite this