1. Dynamic Incorporation of Histone H3 Variants into Chromatin Is Essential for Acquisition of Aggressive Traits and Metastatic Colonization
- Author
-
Sejeong Shin, Noah Dephoure, Edouard Mullarky, Lewis C. Cantley, Sang-Oh Yoon, Paola Cavaliere, Adam Rosenzweig, Vivien Low, Zih-Jie Shen, Ekrem Emrah Er, Joan Massagué, Jessica K. Tyler, Dylan R. McNally, John Blenis, Didem Ilter, Tanya Schild, Michal J. Nagiec, Ana P. Gomes, Julie Han, Anders P. Mutvei, Yi-Hung Ou, Martín A. Rivas, and Ari Melnick
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Epithelial-Mesenchymal Transition ,Carcinogenesis ,Chromatin remodeling ,Article ,Epigenesis, Genetic ,Histones ,03 medical and health sciences ,Histone H3 ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,Animals ,Humans ,Epigenetics ,RNA-Seq ,Neoplasm Metastasis ,Promoter Regions, Genetic ,Transcription factor ,CAF-1 complex ,Regulation of gene expression ,biology ,Carcinoma ,Cell Biology ,Xenograft Model Antitumor Assays ,Chromatin ,Cell biology ,Gene Expression Regulation, Neoplastic ,Chromatin Assembly Factor-1 ,030104 developmental biology ,Histone ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Disease Progression ,Female ,Transcription Factors - Abstract
Metastasis is the leading cause of cancer mortality. Chromatin remodeling provides the foundation for the cellular reprogramming necessary to drive metastasis. However, little is known about the nature of this remodeling and its regulation. Here, we show that metastasis-inducing pathways regulate histone chaperones to reduce canonical histone incorporation into chromatin, triggering deposition of H3.3 variant at the promoters of poor-prognosis genes and metastasis-inducing transcription factors. This specific incorporation of H3.3 into chromatin is both necessary and sufficient for the induction of aggressive traits that allow for metastasis formation. Together, our data clearly show incorporation of histone variant H3.3 into chromatin as a major regulator of cell fate during tumorigenesis, and histone chaperones as valuable therapeutic targets for invasive carcinomas.
- Published
- 2019