Global Regulation of the Histone Mark H3K36me2 Underlies Epithelial Plasticity and Metastatic Progression
| Autor: | Irfan A. Asangani, Jeffrey H. Lin, Yogev Sela, Benjamin A. Garcia, Emma M. Miller, Stacy K. Thomas, Salina Yuan, Jinyang Li, Natarajan V. Bhanu, Ben Z. Stanger, Ramakrishnan Natesan, Taiji Yamazoe, Junwei Shi, Jacqueline B Plesset, Scott W. Lowe, Allyson J. Merrell, Francisco J. Sánchez-Rivera, Yanqing Jiang |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Epithelial-Mesenchymal Transition Biology Article Metastasis Histones 03 medical and health sciences 0302 clinical medicine Neoplasms Transcriptional regulation medicine Humans CRISPR Epigenetics Enhancer Transcription factor Mechanism (biology) Histone-Lysine N-Methyltransferase medicine.disease Cell biology Gene Expression Regulation Neoplastic 030104 developmental biology Histone Oncology 030220 oncology & carcinogenesis biology.protein |
| Zdroj: | Cancer Discov |
| ISSN: | 2159-8290 2159-8274 |
| DOI: | 10.1158/2159-8290.cd-19-1299 |
| Popis: | 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. Significance: Although epithelial plasticity contributes to cancer metastasis and chemoresistance, no strategies exist for pharmacologically inhibiting the process. Here, we show that global regulation of a specific histone mark, H3K36me2, is a universal epigenome-wide mechanism that underlies epithelial-to-mesenchymal transition and mesenchymal-to-epithelial transition in carcinoma cells. These results offer a new strategy for targeting epithelial plasticity in cancer. This article is highlighted in the In This Issue feature, p. 747 |
| Databáze: | OpenAIRE |
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