Human Steroid Sulfatase Enhances Aerobic Glycolysis Through Induction Of Hif1 Alpha And Glycolytic Enzymes
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE(2019)
摘要
Human steroid sulfatase (STS) has been linked with poor prognosis in steroid-associated tumors and represents an important clinical target in cancers, yet the mechanism of STS-induced carcinogenesis remains unclear. To correlate STS with cancer metabolism, we determined the effects of STS on aerobic glycolysis. STS over expression increased cellular levels of lactic acid, the final product of aerobic glycolysis. Moreover, STS suppressed the oxygen consumption rate (OCR), which represents mitochondrial respiration. Inhibition of STS by the specific inhibitor STX064 recovered STS-induced OCR repression and lactic acid over-production. DHEA, but not DHEA-S, suppressed the OCR level and enhanced lactic acid production. To understand the molecular mechanism of STS-induced cancer metabolism, we measured the expression of glycolytic enzymes hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2), which was highly upregulated by STS and DHEA at both protein and mRNA levels. HIF1 alpha is a key mediator of aerobic glycolysis, and STS enhanced HIF1a promoter activity, mRNA expression, and protein expression. Down-regulation of HIF1 alpha by siRNA suppressed the HK2 and PKM2 expression induced by both STS and DHEA. HIF1 alpha siRNA also recovered the OCR repression and lactic acid overproduction induced by both STS and DHEA. To explore the mechanism in vivo, we produced transgenic mice overexpressing STS and found that STS expression was particularly enhanced in the lung. Consistent with our in vitro results, the expression of HIF1 alpha, HK2, and PKM2 was also increased in mouse lung tissues. In conclusion, we suggest that STS may induce aerobic glycolysis through enhancing HIF1 alpha expression.
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关键词
Steroid sulfatase,Dehydroepiandrosterone,Aerobic glycolysis,Hypoxia inducing factor 1 alpha,Hexokinase 2,Pyruvate kinase M2
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