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.

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.