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. 2019 Oct 14;36(4):402-417.e13.
doi: 10.1016/j.ccell.2019.08.006. Epub 2019 Sep 26.

Dynamic Incorporation of Histone H3 Variants Into Chromatin Is Essential for Acquisition of Aggressive Traits and Metastatic Colonization

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Free PMC article

Dynamic Incorporation of Histone H3 Variants Into Chromatin Is Essential for Acquisition of Aggressive Traits and Metastatic Colonization

Ana P Gomes et al. Cancer Cell. .
Free PMC article

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.

Keywords: CAF-1 complex; HIRA; chromatin remodeling; epigenetics; histone H3.3; histone chaperones; metastasis; tumor progression.

Conflict of interest statement

Declaration of Interests

J.M. is a scientific advisor and owns company stock in Scholar Rock. A.M.M. receives research funding from Janssen and has consulted for Epizyme and Constellation. L.C.C. owns equity in, receives compensation from, and serves on the Board of Directors and Scientific Advisory Board of Agios Pharmaceuticals and Petra Pharma Corporation. No potential conflicts of interest were disclosed by the other authors.

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