2. Academic Validation
  3. SUMOylation controls the binding of hexokinase 2 to mitochondria and protects against prostate cancer tumorigenesis

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

  • Nat Commun. 2021 Mar 22;12(1):1812. doi: 10.1038/s41467-021-22163-7.
Xun Shangguan  # 1,  Jianli He  # 1 2,  Zehua Ma 1,  Weiwei Zhang 1,  Yiyi Ji 1,  Kai Shen 1,  Zhiying Yue 1,  Wenyu Li 1,  Zhixiang Xin 1,  Quan Zheng 2,  Ying Cao 2,  Jiahua Pan 1,  Baijun Dong 1,  Jinke Cheng 3 4,  Qi Wang 5,  Wei Xue 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncogenes and Related Genes, Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 2 Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 State Key Laboratory of Oncogenes and Related Genes, Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. jkcheng@shsmu.edu.cn.
  • 4 Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. jkcheng@shsmu.edu.cn.
  • 5 State Key Laboratory of Oncogenes and Related Genes, Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. wqi@sjtu.edu.cn.
  • 6 State Key Laboratory of Oncogenes and Related Genes, Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. xuewei@renji.com.
  • # Contributed equally.
PMID: 33753739 DOI: 10.1038/s41467-021-22163-7
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.

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