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.
Highlights
Human hexokinase 2 is an essential regulator of glycolysis that couples metabolic and proliferative activities in cancer cells
Hexokinases (HK), the first ratelimiting enzymes of glycolysis, catalyze the conversion of glucose to glucose-6-phosphate. This irreversible enzymatic reaction is of fundamental importance because it traps glucose inside cells and because its product glucose-6-phosphate is at the convergence point of glycolysis, the pentose phosphate pathway, the hexosamine pathway, and glycogen synthesis
We aimed to explore the role of HK2 SUMOylation in the modulation of its subcellular trafficking, especially during chemotherapy in prostate cancer
Summary
Human hexokinase 2 is an essential regulator of glycolysis that couples metabolic and proliferative activities in cancer cells. 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. HK1 is constitutively expressed in multiple tissues; HK2 is expressed in embryonic tissue and aggressive tumors, such as lung cancer, hepatocyte cell cancer, breast cancer, and prostate cancer[2,3,4]; HK3 and HK5 (known as HKDC1) are poorly characterized[5]; HK4, known as glucokinase, is located primarily in the liver and the endocrine pancreas Among these hexokinases, HK2 is predominant in malignant or rapidly proliferating tumors rather than most normal adult tissues. SUMO-defective HK2 preferably binds to mitochondria and enhances glycolysis Our data demonstrate an inverse relationship between the SENP1-HK2 axis and chemotherapy response in human prostate cancer samples
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