Histone H3.1 is a chromatin-embedded redox sensor triggered by tumor cells developing adaptive phenotypic plasticity and multidrug resistance. Cell Rep 2024 Mar 26;43(3):113897
Date
03/17/2024Pubmed ID
38493478DOI
10.1016/j.celrep.2024.113897Scopus ID
2-s2.0-85188001867 (requires institutional sign-in at Scopus site)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.
Author List
Palma FR, Coelho DR, Pulakanti K, Sakiyama MJ, Huang Y, Ogata FT, Danes JM, Meyer A, Furdui CM, Spitz DR, Gomes AP, Gantner BN, Rao S, Backman V, Bonini MGAuthors
Benjamin N. Gantner PhD Assistant Professor in the Medicine department at Medical College of WisconsinSridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Breast NeoplasmsChromatin
Drug Resistance, Multiple
Female
Histones
Humans
Hydrogen Peroxide
