Histone Demethylase JMJD1A Regulates Bladder Cancer Cell Glucose Metabolism Through Coactivation Of Hypoxia Inducible Factor 1?

Bladder cancer is a malignant tumor in the urinary bladder,and the incidence is highest in the genitourinary system tumors of China.JMJD1A is a histone demethylase which specifically remove H3K9me1/2.JMJD1A is highly expressed in lots of cancer including bladder cancer.This study showed that JMJD1A can promote cell proliferation in bladder cancer cell lines T24 and 5637,by affecting the protein expression of c-Myc,PCNA,CyclinD1 which related to cell proliferation.The results of fluorescence quantitative PCR and Western Blot showed that JMJD1A could also regulate the expression of key enzymes of glucose metabolism,such as GLUT1,HK2,PGK1,PGM,LDHA,and MCT4.Further studies found that JMJD1A and HIF-1?interacted with each other,regulated H3K9me2 levels on the HRE region of PGK1 promoter,and promoted PGK1 expression.The demethylase activity of JMJD1A is crucial in regulating PGK1 expression.Transfection of HIF-1? into the stable JMJD1A-knockdown cells increased the protein expression of key glycolysis enzymes,and restored cell proliferation;Transfection of siHIF-1? or siPGK1 into the stable JMJD1A-overexpression cells decreased the protein expression of key glycosis enzymes,inhibited the cell proliferation.These results indicate that JMJD1A cooperates with HIF-1? to enhance glycolysis which leads to increase the proliferation of bladder cancer cells.Taken together,as a histone demethylase,JMJD1A can be recruited to the promoters of the key enzymes of glucose metabolic pathway by HIF-1? in bladder cancer cells,and then regulates the histone methylation level to affect the expression of the enzymes and further adjust the glucose metabolism of bladder cancer cells.Eventually,JMJD1A promotes bladder cancer cell growth and proliferation,suggesting that JMJD1A plays an important role in the pathogenesis and development of bladder cancer.This study presents a new idea and potential molecular target for the treatment of bladder cancer.