Epigenetic regulation of the Warburg effect by H2B monoubiquitination
Epigenetic regulation of the Warburg effect by H2B monoubiquitination
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H2B 单泛素化对 Warburg 效应的表观遗传调控
DOI：
10.1038/s41418-019-0450-2
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发表时间：
2020-05-01
影响因子：
12.4
通讯作者：
Chen, Su
中科院分区：
文献类型：
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作者：
Jing, Yuan-Ya;Cai, Feng-Feng;Chen, Su
癌细胞将其能量代谢系统从线粒体氧化磷酸化（OXPHOS）途径重新编程为葡萄糖依赖性有氧糖酵解途径。这种代谢重编程现象被称为瓦尔堡效应，这是癌症的一个重要标志。然而，这一事件背后或触发这种重编程的详细机制在很大程度上仍不清楚。在这里，我们发现组蛋白H2 B单泛素化（H2 Bub 1）负调控瓦尔堡效应和人肺癌细胞（H1299和A549细胞系）的肿瘤发生可能通过控制多个线粒体呼吸基因的表达，这是必不可少的OXPHOS。此外，我们的工作还表明，丙酮酸激酶M2（PKM 2），糖酵解的限速酶，可以直接与H2 B在体内和体外相互作用，并负调节H2 Bub 1的水平。PKM 2基因敲减对人肺癌细胞增殖和裸鼠移植瘤的抑制作用可通过降低H2 Bub 1水平而部分恢复，这表明PKM 2的致癌功能至少部分是通过控制H2 Bub 1实现的。此外，PKM 2和H2 Bub 1水平在癌症标本中呈负相关。因此，这些发现不仅提供了一种新的机制，触发瓦尔堡效应，是通过表观遗传途径（H2 Bub 1）介导的，但也揭示了一种新的代谢调节剂（PKM 2）的表观遗传标记H2 Bub 1。因此，PKM 2-H2 Bub 1轴可能成为一个有前途的肿瘤治疗靶点。
Cancer cells reprogram their energy metabolic system from the mitochondrial oxidative phosphorylation (OXPHOS) pathway to a glucose-dependent aerobic glycolysis pathway. This metabolic reprogramming phenomenon is known as the Warburg effect, a significant hallmark of cancer. However, the detailed mechanisms underlying this event or triggering this reprogramming remain largely unclear. Here, we found that histone H2B monoubiquitination (H2Bub1) negatively regulates the Warburg effect and tumorigenesis in human lung cancer cells (H1299 and A549 cell lines) likely through controlling the expression of multiple mitochondrial respiratory genes, which are essential for OXPHOS. Moreover, our work also suggested that pyruvate kinase M2 (PKM2), the rate-limiting enzyme of glycolysis, can directly interact with H2B in vivo and in vitro and negatively regulate the level of H2Bub1. The inhibition of cell proliferation and nude mice xenograft of human lung cancer cells induced by PKM2 knockdown can be partially rescued through lowering H2Bub1 levels, which indicates that the oncogenic function of PKM2 is achieved, at least partially, through the control of H2Bub1. Furthermore, PKM2 and H2Bub1 levels are negatively correlated in cancer specimens. Therefore, these findings not only provide a novel mechanism triggering the Warburg effect that is mediated through an epigenetic pathway (H2Bub1) but also reveal a novel metabolic regulator (PKM2) for the epigenetic mark H2Bub1. Thus, the PKM2-H2Bub1 axis may become a promising cancer therapeutic target.