中国医科大学Jer-Yen Yang，Chun Ju Chang和美国雪松-西奈医疗中心Yingsheng Zhang共同合作，近期取得重要工作进展。他们研究发现，代谢转换可调节三阴性乳腺癌谱系可塑性并诱导合成致死。相关研究成果2024年1月2日在线发表于《细胞—代谢》杂志上。

据介绍，代谢重编程是癌症发展的关键，尽管丙酮酸激酶M2（PKM2）和肿瘤糖酵解缺乏，但维持三阴性癌症（TNBC）细胞生长的机制仍有待确定。

研究人员发现肿瘤糖酵解的缺乏激活了从糖酵解到脂肪酸β-氧化（FAO）的代谢转换，以促进TNBC的生长。研究人员发现，在TNBC细胞中，PKM2直接与组蛋白甲基转移酶EZH2相互作用，协同介导肉碱转运蛋白SLC16A9的表观遗传学沉默。PKM2的抑制导致EZH2向SLC16A9的募集受损，进而去抑制SLC16A9的表达以增加细胞内肉碱的流入，将TNBC细胞编程为FAO依赖性和管腔样细胞状态。

总之，这些发现揭示了一种新的代谢转换，它将TNBC从代谢异质性谱系可塑性细胞状态驱动到FAO依赖性谱系细胞状态，在这种状态下，EZH2和FAO的双重靶向诱导TNBC的强效合成致死性。

附：英文原文

Title: Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer

Author: Yingsheng Zhang, Meng-Ju Wu, Wan-Chi Lu, Yi-Chuan Li, Chun Ju Chang, Jer-Yen Yang

Issue&Volume: 2024/01/02

Abstract: Metabolic reprogramming is key for cancer development, yet the mechanism that sustainstriple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinaseM2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiencyin tumor glycolysis activates a metabolic switch from glycolysis to fatty acid β-oxidation(FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts withhistone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitinetransporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitineinflux, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together,these findings reveal a new metabolic switch that drives TNBC from a metabolicallyheterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cellstate, where dual targeting of EZH2 and FAO induces potent synthetic lethality inTNBC.

DOI: 10.1016/j.cmet.2023.12.003

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00455-2