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 Chen; Lauren E Haydu; Wei-Lien Wang; Alexander J Lazar; Scott E Woodman; Chantale Bernatchez; Kunal Rai

doi:10.1016/j.celrep.2021.109410

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

Cell Rep. 2021 Jul 20;36(3):109410. doi: 10.1016/j.celrep.2021.109410.

Authors

Christopher J Terranova¹, Ming Tang², Mayinuer Maitituoheti¹, Ayush T Raman³, Archit K Ghosh¹, Jonathan Schulz¹, Samir B Amin⁴, Elias Orouji⁵, Katarzyna Tomczak¹, Sharmistha Sarkar¹, Junna Oba⁶, Caitlin Creasy⁶, Chang-Jiun Wu¹, Samia Khan⁷, Rossana Lazcano⁷, Khalida Wani⁷, Anand Singh¹, Praveen Barrodia¹, Dongyu Zhao⁸, Kaifu Chen⁹, Lauren E Haydu¹⁰, Wei-Lien Wang¹¹, Alexander J Lazar¹¹, Scott E Woodman¹², Chantale Bernatchez⁶, Kunal Rai¹³

Affiliations

¹ Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
² Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; FAS informatics, Department of Molecular Biology, Harvard, Cambridge, MA 02138, USA.
³ Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Epigenomics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Graduate Program in Quantitative Sciences, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
⁵ Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Epigenetics Initiative, Princess Margaret Genomics Centre, Toronto, ON M5G 2C1, Canada.
⁶ Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
⁷ Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
⁸ Houston Methodist Academic Institute, Methodist Hospital Research Institute, Houston, TX 77030, USA.
⁹ Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA.
¹⁰ Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
¹¹ Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
¹² Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
¹³ Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address: krai@mdanderson.org.

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.

Keywords: Polycomb repressive complex 2; bivalent; broad domains; chromatin; epigenetics; melanoma; melanoma therapeutics; metastasis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation
Chromatin / metabolism*
Enhancer of Zeste Homolog 2 Protein / metabolism
Female
GTP Phosphohydrolases / genetics*
GTP Phosphohydrolases / metabolism
Histones / metabolism
Humans
Melanocytes / metabolism
Melanoma / genetics*
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Mesoderm / metabolism
Mice
Mice, Nude
Mitogen-Activated Protein Kinase Kinases / metabolism
Mutation / genetics*
Neoplasm Metastasis
Polycomb Repressive Complex 2 / antagonists & inhibitors*
Polycomb Repressive Complex 2 / metabolism
Transcription, Genetic
Tumor Burden

Substances

Chromatin
Histones
Membrane Proteins
histone H3 trimethyl Lys4
Enhancer of Zeste Homolog 2 Protein
Ezh2 protein, mouse
Polycomb Repressive Complex 2
Mitogen-Activated Protein Kinase Kinases
GTP Phosphohydrolases
NRAS protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding