Abstract：
Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in 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 with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, 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 metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.
摘要：
代谢重编程是癌症发展的关键，尽管丙酮酸激酶M2(PKM2)缺乏和肿瘤糖酵解,但维持三阴性乳腺癌(TNBC)细胞生长的机制仍有待确定.这里,我们发现肿瘤糖酵解的缺乏会激活从糖酵解到脂肪酸β-氧化（FAO）的代谢转换，从而促进TNBC的生长。我们证明,在TNBC细胞中，PKM2直接与组蛋白甲基转移酶EZH2相互作用，协调介导肉碱转运蛋白的表观遗传沉默，SLC16A9.抑制PKM2会导致SLC16A9的EZH2募集受损，进而抑制SLC16A9表达以增加细胞内肉碱流入，将TNBC细胞编程为FAO依赖性和管腔样细胞状态。一起,这些发现揭示了一种新的代谢开关，将TNBC从代谢异质性谱系塑料细胞状态驱动到FAO依赖的谱系定型细胞状态，其中EZH2和FAO的双重靶向在TNBC中诱导有效的合成致死性。
