State Key Laboratory of Oncogenes and Related Genes, Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Nat Commun. 2021 Mar 22;12(1):1812. doi: 10.1038/s41467-021-22163-7.
Human hexokinase 2 is an essential regulator of glycolysis that couples metabolic and proliferative activities in cancer cells. The binding of hexokinase 2 to the outer membrane of mitochondria is critical for its oncogenic activity. However, the regulation of hexokinase 2 binding to mitochondria remains unclear. Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K492. SUMO-specific protease SENP1 mediates the de-SUMOylation of hexokinase 2. SUMO-defective hexokinase 2 preferably binds to mitochondria and enhances both glucose consumption and lactate production and decreases mitochondrial respiration in parallel. This metabolic reprogramming supports prostate cancer cell proliferation and protects cells from chemotherapy-induced cell apoptosis. Moreover, we demonstrate an inverse relationship between SENP1-hexokinase 2 axis and chemotherapy response in prostate cancer samples. Our data provide evidence for a previously uncovered posttranslational modification of hexokinase 2 in cancer cells, suggesting a potentially actionable strategy for preventing chemotherapy resistance in prostate cancer.
人源己糖激酶 2 是糖酵解的必需调节因子，可将癌细胞的代谢和增殖活性偶联。己糖激酶 2 与线粒体外膜的结合对于其致癌活性至关重要。然而，己糖激酶 2 与线粒体结合的调节仍不清楚。在这里，我们报告 SUMO 化调节己糖激酶 2 与线粒体的结合。我们发现己糖激酶 2 可以在 K315 和 K492 处被 SUMO 化。SUMO 特异性蛋白酶 SENP1 介导己糖激酶 2 的去 SUMO 化。SUMO 缺陷型己糖激酶 2 优先与线粒体结合，并增强葡萄糖消耗和乳酸生成，同时降低线粒体呼吸。这种代谢重编程支持前列腺癌细胞的增殖，并保护细胞免受化疗诱导的细胞凋亡。此外，我们在前列腺癌样本中证明了 SENP1-己糖激酶 2 轴与化疗反应之间的反比关系。我们的数据为癌细胞中己糖激酶 2 的一种以前未被发现的翻译后修饰提供了证据，提示在预防前列腺癌化疗耐药性方面可能有潜在的可行策略。
