马萨诸塞州总医院David T. Scadden课题组的研究发现抑制核丙酮酸脱氢酶诱导治疗性癌细胞重编程。相关论文于2025年6月11日发表在《细胞—代谢》杂志上。

小组报告了一种核核特异性乙酰辅酶A调节机制，可以调节以实现治疗性癌细胞重编程。结合表型化学筛选、全基因组CRISPR筛选和蛋白质组学，该课题组发现核位丙酮酸脱氢酶复合物（nPDC）通过直接相互作用受到核蛋白ELMSAN1的组成性抑制。药物抑制ELMSAN1-nPDC相互作用可抑制nPDC活性，增强核乙酰辅酶A的生成，并将癌细胞重编程为有丝分裂后状态，减少细胞起源特征。组蛋白去乙酰化酶1/2抑制可协同增强重编程，从而抑制肿瘤生长，持久抑制肿瘤启动能力，并提高体内多种癌症类型的生存率，包括治疗抵抗性肉瘤患者来源的异种移植物和癌细胞系的异种移植物。他们的发现强调了靶向ELMSAN1-nPDC作为表观遗传癌症治疗的潜力。

据了解，代谢物是表观遗传修饰的基本底物。尽管核乙酰辅酶A（CoA）只占整个细胞池的一小部分，但它通过局部提供组蛋白乙酰化底物来调节细胞命运。

附：英文原文

Title: Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming

Author: Ting Zhao, Lingli He, Lai Ping Wong, Shenglin Mei, Jun Xia, Yanxin Xu, Jonathan G. Van Vranken, Michael Mazzola, Lei Chen, Catherine Rhee, Tiancheng Fang, Tsuyoshi Fukushima, Leanne C. Sayles, Matthew Diaz, J. Alex B. Gibbons, Raul Mostoslavsky, Steven P. Gygi, Zhixun Dou, David B. Sykes, Ruslan I. Sadreyev, E. Alejandro Sweet-Cordero, David T. Scadden

Issue&Volume: 2025-06-11

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.

DOI: 10.1016/j.cmet.2025.05.009

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00265-7