SUMOylation controls the binding of hexokinase 2 to mitochondria and protects against prostate cancer tumorigenesis

Xun Shangguan, Jianli He, Zehua Ma, Weiwei Zhang, Yiyi Ji, Kai Shen, Zhiying Yue, Wenyu Li, Zhixiang Xin, Quan Zheng, Ying Cao, Jiahua Pan, Baijun Dong, Jinke Cheng (), Qi Wang () and Wei Xue ()
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Xun Shangguan: Shanghai Jiao Tong University
Jianli He: Shanghai Jiao Tong University
Zehua Ma: Shanghai Jiao Tong University
Weiwei Zhang: Shanghai Jiao Tong University
Yiyi Ji: Shanghai Jiao Tong University
Kai Shen: Shanghai Jiao Tong University
Zhiying Yue: Shanghai Jiao Tong University
Wenyu Li: Shanghai Jiao Tong University
Zhixiang Xin: Shanghai Jiao Tong University
Quan Zheng: Shanghai Jiao Tong University School of Medicine
Ying Cao: Shanghai Jiao Tong University School of Medicine
Jiahua Pan: Shanghai Jiao Tong University
Baijun Dong: Shanghai Jiao Tong University
Jinke Cheng: Shanghai Jiao Tong University
Qi Wang: Shanghai Jiao Tong University
Wei Xue: Shanghai Jiao Tong University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-22163-7

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