Global Regulation of the Histone Mark H3K36me2 Underlies Epithelial Plasticity and Metastatic Progression
Abstract
Epithelial plasticity, reversible modulation of a cell's epithelial and mesenchymal features, is associated with tumor metastasis and chemoresistance, leading causes of cancer mortality. Although different master transcription factors and epigenetic modifiers have been implicated in this process in various contexts, the extent to which a unifying, generalized mechanism of transcriptional regulation underlies epithelial plasticity remains largely unknown. Here, through targeted CRISPR/Cas9 screening, we discovered two histone-modifying enzymes involved in the writing and erasing of H3K36me2 that act reciprocally to regulate epithelial-to-mesenchymal identity, tumor differentiation, and metastasis. Using a lysine-to-methionine histone mutant to directly inhibit H3K36me2, we found that global modulation of the mark is a conserved mechanism underlying the mesenchymal state in various contexts. Mechanistically, regulation of H3K36me2 reprograms enhancers associated with master regulators of epithelial-to-mesenchymal state. Our results thus outline a unifying epigenome-scale mechanism by which a specific histone modification regulates cellular plasticity and metastasis in cancer.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 01, 2020
- Source ID
- 10.1158/2159-8290.cd-19-1299
Entities
People
- Allyson J. Merrell
- Ben Z Stanger
- Benjamin A Garcia
- Emma M. Miller
- Francisco J Sánchez-Rivera
- Irfan A. Asangani
- Jacqueline B. Plesset
- Jeffrey H. Lin
- Jinyang Li
- Junwei Shi
- Natarajan V. Bhanu
- Ramakrishnan Natesan
- Salina Yuan
- Scott W. Lowe
- Stacy Thomas
- Taiji Yamazoe
- Yanqing Jiang
- Yogev Sela
Organizations
- Abramson Cancer Center
- Abramson Family Cancer Research Institute
- Memorial Sloan Kettering Cancer Center
- National Institutes of Health
- United States Department of Defense
- University of Pennsylvania
- V Foundation for Cancer Research