Document Type
Article
Publication Date
7-20-2021
Publication Title
Cell Rep
Keywords
JGM
JAX Source
Cell Rep 2021 Jul 20; 36(3):109410
Volume
36
Issue
3
First Page
109410
Last Page
109410
ISSN
2211-1247
PMID
34289358
DOI
https://doi.org/10.1016/j.celrep.2021.109410
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.
Recommended Citation
Terranova C,
Tang M,
Maitituoheti M,
Raman A,
Ghosh A,
Schulz J,
Amin S,
Orouji E,
Tomczak K,
Sarkar S,
Oba J,
Creasy C,
Wu C,
Khan S,
Lazcano R,
Wani K,
Singh A,
Barrodia P,
Zhao D,
Chen K,
Haydu L,
Wang W,
Lazar A,
Woodman S,
Bernatchez C,
Rai K.
Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy. Cell Rep 2021 Jul 20; 36(3):109410
Comments
This is an Open Access article distributed under the terms of the Creative Commons Attribution License.