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

doi:10.1016/j.celrep.2024.113897

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

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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 language	English (US)
Article number	113897
Journal	Cell reports
Volume	43
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2024.113897
State	Published - Mar 26 2024

Funding

This project was supported by National Cancer Institute grants R01CA216882 (to M.G.B.), U54268084 and U54261694 (to V.B.), R01CA225002 (to V.B.); National Institute of Environmental Health Sciences grants R01ES035723 and R01ES028149 (both to M.G.B.); National Institute of Allergy and Infectious Diseases grant R01AI131267 (to M.G.B.); National Heart, Lung and Blood Institute grants R01HL163820 (to M.G.B.) and P01HL149620 (to S.R.); and National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK134064 (to S.R.). We are also grateful for the financial support from the Lefkofsky Foundation Innovator Award (to M.G.B. and V.B.). We are also grateful to Northwestern University Center for Advanced Microscopy (CAM), Quantitative Data Sciences Core (QDSC) and NUSeq for technical assistance. Conceptualization: F.R.P. B.N.G. S.R. V.B. and M.G.B. Investigation: F.R.P. D.R.C. K.P. M.J.S. F.T.O. Y.H. J.M.D. A.M. and M.G.B. Formal analysis: F.R.P. D.R.C. and K.P. Methodology: F.R.P. C.M.F. D.R.S. A.P.G. B.N.G. S.R. V.B. and M.G.B. Visualization: F.R.P. and K.P. Writing: F.R.P. D.R.S. A.P.G. B.N.G. and M.G.B. The authors declare no competing interests. This project was supported by National Cancer Institute grants R01CA216882 (to M.G.B.), R01CA228272 (to V.B.), R01CA225002 (to V.B.), and P30CA060553 (to V.B.); National Institute of Environmental Health Sciences grants R01ES035723 and R01ES028149 (both to M.G.B.); National Institute of Allergy and Infectious Diseases grant R01AI131267 (to M.G.B.); National Heart, Lung and Blood Institute grants R01HL163820 (to M.G.B.) and P01HL149620 (to S.R.); and National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK134064 (to S.R.). We are also grateful for the financial support from the Lefkofsky Foundation Innovator Award (to M.G.B. and V.B.).

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2024.113897

Cite this

Palma, F. R., Coelho, D. R., Pulakanti, K., Sakiyama, M. J., Huang, Y., Ogata, F. T., Danes, J. M., Meyer, A., Furdui, C. M., Spitz, D. R., Gomes, A. P., Gantner, B. N., Rao, S., Backman, V., & Bonini, M. G. (2024). Histone H3.1 is a chromatin-embedded redox sensor triggered by tumor cells developing adaptive phenotypic plasticity and multidrug resistance. Cell reports, 43(3), Article 113897. https://doi.org/10.1016/j.celrep.2024.113897

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

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.",

keywords = "CP: Cancer, EMT, H3, ROS, breast cancer, chemoresistance, drug resistance, histone variants, metastasis, redox, thiol oxidation",

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

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

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doi = "10.1016/j.celrep.2024.113897",

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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, MG 2024, 'Histone H3.1 is a chromatin-embedded redox sensor triggered by tumor cells developing adaptive phenotypic plasticity and multidrug resistance', Cell reports, vol. 43, no. 3, 113897. https://doi.org/10.1016/j.celrep.2024.113897

TY - JOUR

T1 - Histone H3.1 is a chromatin-embedded redox sensor triggered by tumor cells developing adaptive phenotypic plasticity and multidrug resistance

AU - Palma, Flavio R.

AU - Coelho, Diego R.

AU - Pulakanti, Kirthi

AU - Sakiyama, Marcelo J.

AU - Huang, Yunping

AU - Ogata, Fernando T.

AU - Danes, Jeanne M.

AU - Meyer, Alison

AU - Furdui, Cristina M.

AU - Spitz, Douglas R.

AU - Gomes, Ana P.

AU - Gantner, Benjamin N.

AU - Rao, Sridhar

AU - Backman, Vadim

AU - Bonini, Marcelo G.

PY - 2024/3/26

Y1 - 2024/3/26

N2 - 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.

AB - 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.

KW - CP: Cancer

KW - EMT

KW - H3

KW - ROS

KW - breast cancer

KW - chemoresistance

KW - drug resistance

KW - histone variants

KW - metastasis

KW - redox

KW - thiol oxidation

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UR - http://www.scopus.com/inward/citedby.url?scp=85188001867&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2024.113897

DO - 10.1016/j.celrep.2024.113897

M3 - Article

C2 - 38493478

AN - SCOPUS:85188001867

SN - 2211-1247

VL - 43

JO - Cell reports

JF - Cell reports

IS - 3

M1 - 113897

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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