PRMT5 competitively binds to CDK4 to promote G1-S transition upon glucose induction in hepatocellular carcinoma
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Hao Yang1, Xiaoping Zhao2, Li Zhao2, Liu Liu2, Jiajin Li2, Wenzhi Jia2, Jianjun Liu2, Gang Huang1,2,3,4
1Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200031, China
2Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
3Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
4Shanghai University of Medicine and Health Sciences, Shanghai 201318, China
Gang Huang, email: firstname.lastname@example.org
Keywords: glucose, PRMT5, cell cycle progression, competitive binding, hepatocellular carcinoma
Received: December 14, 2015 Accepted: September 20, 2016 Published: September 30, 2016
Although cancer cells are known to be “addicted” to glucose, the effect of glucose in proliferation of these cells remains elusive. Here, we report that upon glucose induction, protein arginine methyltransferase 5 (PRMT5) exerts a profound effect on the G1-S cell cycle progression via directly interacting with cyclin dependent kinase 4 (CDK4) in hepatocellular carcinoma (HCC). Upregulation of both PRMT5 and CDK4 predicts more malignant characteristics in human HCC tissues. Mechanistically, glucose promotes the interaction between PRMT5 and CDK4, which leads to activation of CDK4-RB-E2F-mediated transcription via releasing CDKN2A from CDK4. Moreover, the PRMT5 competitive inhibition of the interaction between CDK4 and CDKN2A is important for glucose-induced growth of HCC cells. Furthermore, the CDK4 mutant R24A weakly binds to PRMT5, inhibiting HCC cell cycle progression and tumor growth. Thus, our findings uncover a critical function for PRMT5 and CDK4 and provide an improved therapeutic strategy against HCC.
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