SUMOylation controls the binding of hexokinase 2 to mitochondria and protects against prostate cancer tumorigenesis.
Xun ShangguanJianli HeZehua MaWeiwei ZhangYiyi JiKai ShenZhiying YueWenyu LiZhixiang XinQuan ZhengYing CaoJiahua PanBaijun DongJinke ChengQi WangWei XuePublished in: Nature communications (2021)
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.
Keyphrases
- prostate cancer
- radical prostatectomy
- reactive oxygen species
- chemotherapy induced
- endoplasmic reticulum
- endothelial cells
- type diabetes
- oxidative stress
- skeletal muscle
- machine learning
- electronic health record
- locally advanced
- squamous cell carcinoma
- adipose tissue
- signaling pathway
- big data
- blood glucose
- artificial intelligence