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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Carcinoma / genetics
  • Carcinoma / pathology*
  • Cell Line, Tumor
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Chromatin Assembly Factor-1 / genetics
  • Chromatin Assembly Factor-1 / metabolism
  • Disease Progression
  • Epigenesis, Genetic
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Male
  • Mice
  • Neoplasm Metastasis / genetics*
  • Promoter Regions, Genetic / genetics
  • RNA-Seq
  • Transcription Factors / genetics
  • Xenograft Model Antitumor Assays

Substances

  • CHAF1A protein, human
  • CHAF1B protein, human
  • Chromatin
  • Chromatin Assembly Factor-1
  • Histones
  • Transcription Factors