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Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming [CUT&Tag]

ABSTRACT: Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming [CUT&Tag]

PROVIDER: PRJNA1260415 | ENA |

REPOSITORIES: ENA

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Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming (H3K27ac Cut&Tag)

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Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming [CUT&Tag]

Project description:Metabolites are essential substrates for epigenetic modifications. Although nuclear acetyl-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 reprograming 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 epigenetic cancer therapy.

2025-05-09 | GSE296631 | GEO