Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming

Ting Zhao¹, Lingli He², Lai Ping Wong³, Shenglin Mei⁴, Jun Xia², Yanxin Xu⁴, Jonathan G Van Vranken⁵, Michael Mazzola², Lei Chen², Catherine Rhee², Tiancheng Fang², Tsuyoshi Fukushima², Leanne C Sayles⁶, Matthew Diaz², J Alex B Gibbons², Raul Mostoslavsky⁷, Steven P Gygi⁵, Zhixun Dou⁴, David B Sykes⁴, Ruslan I Sadreyev⁸, E Alejandro Sweet-Cordero⁶, David T Scadden⁹

Affiliations

¹ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. Electronic address: tzhao4@mgh.harvard.edu.
² Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
³ Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA.
⁵ Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
⁶ Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
⁷ Krantz Family Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁹ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. Electronic address: david_scadden@harvard.edu.

PMID: 40505660
DOI: 10.1016/j.cmet.2025.05.009

Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming

Ting Zhao et al. Cell Metab. 2025.

. 2025 Aug 5;37(8):1667-1681.e13.

doi: 10.1016/j.cmet.2025.05.009. Epub 2025 Jun 11.

Authors

Affiliations

¹ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. Electronic address: tzhao4@mgh.harvard.edu.
² Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
³ Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA.
⁵ Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
⁶ Division of Hematology and Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
⁷ Krantz Family Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁹ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. Electronic address: david_scadden@harvard.edu.

PMID: 40505660
DOI: 10.1016/j.cmet.2025.05.009

Abstract

Metabolites are essential substrates for epigenetic modifications. Although nuclear acetyl-coenzyme A (CoA) constitutes a small fraction of the whole-cell pool, it regulates cell fate by locally providing histone acetylation substrate. Here, we report a nucleus-specific acetyl-CoA regulatory mechanism that can be modulated to achieve therapeutic cancer cell reprogramming. Combining phenotypic chemical screen, genome-wide CRISPR screen, and proteomics, we identified that the nucleus-localized pyruvate dehydrogenase complex (nPDC) is constitutively inhibited by the nuclear protein ELMSAN1 through direct interaction. Pharmacologic inhibition of the ELMSAN1-nPDC interaction derepressed nPDC activity, enhancing nuclear acetyl-CoA generation and reprogramming cancer cells to a postmitotic state with diminished cell-of-origin signatures. Reprogramming was synergistically enhanced by histone deacetylase 1/2 inhibition, resulting in inhibited tumor growth, durably suppressed tumor-initiating ability, and improved survival in multiple cancer types in vivo, including therapy-resistant sarcoma patient-derived xenografts and carcinoma cell line xenografts. Our findings highlight the potential of targeting ELMSAN1-nPDC as an epigenetic cancer therapy.

Keywords: ELMSAN1; HDAC; ISX9; acetyl-CoA metabolism; cancer therapy; compartmentalized metabolism; epigenetic reprogramming; nuclear metabolism; pyruvate dehydrogenase complex; therapeutic reprogramming.

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Conflict of interest statement

Declaration of interests Harvard has filed a provisional patent application based on this work. D.B.S.: Clear Creek Bio: current holder of individual stocks in a privately held company. D.T.S.: Agios Pharmaceuticals: membership on an entity's Board of Directors or advisory committees; Editas Medicines: membership on an entity’s Board of Directors or advisory committees; Garuda Therapeutics: current holder of individual stocks in a privately held company and membership on an entity's Board of Directors or advisory committees; Clear Creek Bio: current holder of individual stocks in a privately held company; Sonata Therapeutics: current holder of individual stocks in a privately held company, membership on an entity's Board of Directors or advisory committees; Lightning Biotherapeutics: current holder of individual stocks in a privately held company, membership on an entity's Board of Directors or advisory committees; Carisma Therapeutics: current holder of individual stocks in a privately held company and membership on an entity's Board of Directors or advisory committees; and VCanBio: consultancy.

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Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming

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Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming

Authors

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Abstract

Conflict of interest statement

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Medical