Histone H3.1 is a chromatin-embedded redox sensor triggered by tumor cells developing adaptive phenotypic plasticity and multidrug resistance

Flavio R. Palma, Diego R. Coelho, Kirthi Pulakanti, Marcelo J. Sakiyama, Yunping Huang, Fernando T. Ogata, Jeanne M. Danes, Alison Meyer, Cristina M. Furdui, Douglas R. Spitz, Ana P. Gomes, Benjamin N. Gantner, Sridhar Rao, Vadim Backman, Marcelo G. Bonini*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Chromatin structure is regulated through posttranslational modifications of histone variants that modulate transcription. Although highly homologous, histone variants display unique amino acid sequences associated with specific functions. Abnormal incorporation of histone variants contributes to cancer initiation, therapy resistance, and metastasis. This study reports that, among its biologic functions, histone H3.1 serves as a chromatin redox sensor that is engaged by mitochondrial H2O2. In breast cancer cells, the oxidation of H3.1Cys96 promotes its eviction and replacement by H3.3 in specific promoters. We also report that this process facilitates the opening of silenced chromatin domains and transcriptional activation of epithelial-to-mesenchymal genes associated with cell plasticity. Scavenging nuclear H2O2 or amino acid substitution of H3.1(C96S) suppresses plasticity, restores sensitivity to chemotherapy, and induces remission of metastatic lesions. Hence, it appears that increased levels of H2O2 produced by mitochondria of breast cancer cells directly promote redox-regulated H3.1-dependent chromatin remodeling involved in chemoresistance and metastasis.

Original languageEnglish (US)
Article number113897
JournalCell reports
Volume43
Issue number3
DOIs
StatePublished - Mar 26 2024

Keywords

  • CP: Cancer
  • EMT
  • H3
  • ROS
  • breast cancer
  • chemoresistance
  • drug resistance
  • histone variants
  • metastasis
  • redox
  • thiol oxidation

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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