Journal article
Histone H3.1 is a chromatin-embedded redox sensor triggered by tumor cells developing adaptive phenotypic plasticity and multidrug resistance
Cell reports (Cambridge), Vol.43(3), 113897
03/26/2024
DOI: 10.1016/j.celrep.2024.113897
PMCID: PMC11209755
PMID: 38493478
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.
[Display omitted]
•Cysteine oxidation is a functional modification of the H3.1 histone variant•H3.1Cys96 oxidation promotes its exchange by H3.3•H3.1Cys96 oxidation promotes multidrug resistance in breast cancer•H3.1Cys96 modification by ROS promotes metastasis
Palma et al. report that H3.1Cys96 oxidation is a functional posttranslational modification involved in the regulation of gene expression. In breast cancer, H3.1Cys96 oxidation promotes resistance to first-line chemotherapeutic drugs and stimulates metastasis. They also show that suppressing H3.1Cys96 oxidation inhibits metastasis while resensitizing cancer cells to chemotherapy.
Details
- Title: Subtitle
- Histone H3.1 is a chromatin-embedded redox sensor triggered by tumor cells developing adaptive phenotypic plasticity and multidrug resistance
- Creators
- Flavio R. Palma - Department of Medicine, Division of Hematology Oncology, Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Chicago, Chicago, IL 60611, USADiego R. Coelho - Department of Medicine, Division of Hematology Oncology, Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Chicago, Chicago, IL 60611, USAKirthi Pulakanti - Versiti Blood Center of WisconsinMarcelo J. Sakiyama - Department of Medicine, Division of Hematology Oncology, Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Chicago, Chicago, IL 60611, USAYunping Huang - Department of Medicine, Division of Hematology Oncology, Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Chicago, Chicago, IL 60611, USAFernando T. Ogata - Department of Medicine, Division of Hematology Oncology, Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Chicago, Chicago, IL 60611, USAJeanne M. Danes - Department of Medicine, Division of Hematology Oncology, Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Chicago, Chicago, IL 60611, USAAlison Meyer - Versiti Blood Research Institute of Wisconsin, and Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USACristina M. Furdui - Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USADouglas R. Spitz - University of Iowa, Fraternal Order of Eagles Diabetes Research CenterAna P. Gomes - Molecular Oncology Program, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USABenjamin N. Gantner - Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USASridhar Rao - Versiti Blood Research Institute of Wisconsin, and Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USAVadim Backman - Department of Biomedical Engineering, Northwestern University McCormick School of Engineering, Evanston, IL 60208, USAMarcelo G. Bonini - Department of Medicine, Division of Hematology Oncology, Northwestern University Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Chicago, Chicago, IL 60611, USA
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.43(3), 113897
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.celrep.2024.113897
- PMID
- 38493478
- PMCID
- PMC11209755
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Language
- English
- Date published
- 03/26/2024
- Academic Unit
- Pathology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984648256602771
Metrics
6 Record Views