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

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

doi:10.1016/j.celrep.2021.109410

Abstract

SUMMARYThe 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.

Highlights

Melanoma is a deadly disease with an estimated 100,000 new cases each year in the United States (Lens and Dawes, 2004; Miller and Mihm, 2006)
We identified enhancers (H3K27ac and H3K4me1), promoters (H3K4me3), actively transcribed loci (H3K79me2), polycomb silenced loci (H3K27me3), and heterochromatin (H3K9me3) elements in 46 melanoma samples by ChIP-seq using a highthroughput ChIP-seq protocol adapted for tumor tissues (Terranova et al, 2018)
These constituted 20 metastatic melanoma tumors (TCGA [Cancer Genome Atlas Network, 2015]), 10 patient-derived melanoma short-term cultures (MSTCs; passage n < 10; profiled by internal effort at MD Anderson; unpublished data), and 16 established melanoma lines profiled by the Cancer Cell Line Encyclopedia/Sanger (CCLE) (Barretina et al, 2012) (Table S1)

Summary

Introduction

Melanoma is a deadly disease with an estimated 100,000 new cases each year in the United States (Lens and Dawes, 2004; Miller and Mihm, 2006). Large-scale efforts from consortiums such as The Cancer Genome Atlas (TCGA) have provided deeper understanding of molecular aberrations in metastatic melanoma (Cancer Genome Atlas Network, 2015; Hodis et al, 2012; Tsao et al, 2012). These studies identified critical somatic mutations in this disease that likely occur due to UV exposure.

Results

Discussion

Conclusion