Interrupting Elmsan1 repression of nuclear Acetyl-CoA production therapeutically reprograms cancer cells

Zhao, T.; He, L.; Wong, L. P.; Mei, S.; Xia, J.; Xu, Y.; Van Vranken, J.; Mazzola, M.; Chen, L.; Rhee, C.; Fang, T.; Fukushima, T.; Sayles, L.; Diaz, M.; Gibbons, J. A. B.; Mostoslavsky, R.; Gygi, S. P.; Dou, Z.; Sykes, D. B.; Sadreyev, R.; Sweet-Cordero, A.; Scadden, D. T.

doi:10.1101/2025.04.25.650293

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bioRxiv · 10.1101/2025.04.25.650293

Interrupting Elmsan1 repression of nuclear Acetyl-CoA production therapeutically reprograms cancer cells

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Abstract

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 combined phenotypic chemical screen and genome-wide CRISPR screen to demonstrate a nucleus-specific acetyl-CoA regulatory mechanism that can be modulated to achieve therapeutic cancer cell reprogramming. While previously thought that nucleus-localized pyruvate dehydrogenase complex (nPDC) is constitutively active, we found that 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 epigenetic cancer therapy.

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Zhao, T., He, L., Wong, L. P., Mei, S., Xia, J., Xu, Y., Van Vranken, J., Mazzola, M., Chen, L., Rhee, C., Fang, T., Fukushima, T., Sayles, L., Diaz, M., Gibbons, J. A. B., Mostoslavsky, R., Gygi, S. P., Dou, Z., Sykes, D. B., Sadreyev, R., Sweet-Cordero, A., Scadden, D. T.. 2025-04-29. Interrupting Elmsan1 repression of nuclear Acetyl-CoA production therapeutically reprograms cancer cells. https://doi.org/10.1101/2025.04.25.650293

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