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

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.
Christopher J Terranova 1,  Ming Tang 2,  Mayinuer Maitituoheti 1,  Ayush T Raman 3,  Archit K Ghosh 1,  Jonathan Schulz 1,  Samir B Amin 4,  Elias Orouji 5,  Katarzyna Tomczak 1,  Sharmistha Sarkar 1,  Junna Oba 6,  Caitlin Creasy 6,  Chang-Jiun Wu 1,  Samia Khan 7,  Rossana Lazcano 7,  Khalida Wani 7,  Anand Singh 1,  Praveen Barrodia 1,  Dongyu Zhao 8,  Kaifu Chen 9,  Lauren E Haydu 10,  Wei-Lien Wang 11,  Alexander J Lazar 11,  Scott E Woodman 12,  Chantale Bernatchez 6,  Kunal Rai 13
Affiliations

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.
PMID: 34289358 DOI: 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.

Keywords

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

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