Abstract
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.
Highlights
Liver cancer, especially hepatocellular carcinoma (HCC), causes high morbidity and mortality relative to other cancers [1]
These results indicated that the protein levels of protein arginine methyltransferase 5 (PRMT5) and cyclin dependent kinase 4 (CDK4) are positively correlated in human HCC tissues, which predict more malignant characteristics
Since PRMT5 was needed for CDK4 1-70 aa binding and inhibited the binding between CDK4 and CDKN2A, we examined whether PRMT5 and CDKN2A competitively interact with CDK4 1-70 aa
Summary
Especially hepatocellular carcinoma (HCC), causes high morbidity and mortality relative to other cancers [1]. Major precipitating factors for hepatocarcinogenesis include hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, chemical cytotoxicity and aberrant hepatic metabolism [2,3,4]. Hepatectomy has been identified as the main treatment strategy for HCC, poor prognosis still frequently exists [5]. The need to explore underlying therapeutic options and molecular targets is urgent. Since aberrant progression of the cyclin dependent kinase (CDK)-driven cell cycle is one of the hallmarks of cancers [6], many studies have focused on these cell cycle regulators as potential targets in HCC. Among the CDKs, cyclin dependent kinase 4 (CDK4) plays a specific role in tumorigenesis and development [7]. Combined with cyclin D (CCND), CDK4 controls cancer cells from the
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