title: PRMT5 competitively binds to CDK4 to promote G1-S transition upon glucose induction in hepatocellular carcinoma.
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.
authors.affiliation: Institute 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.
authors.forename: Hao
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
authors.forename: Jiajin
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
authors.forename: Wenzhi
authors.initials: W
authors.lastname: Jia
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute 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.|Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.|Institute of Clinical Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.|Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002469:Cell Separation / Q000379:methods; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics / Q000378:metabolism; D050684:E2F Transcription Factors / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D056286:Retinoblastoma Binding Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D000644:Quaternary Ammonium Compounds; D002243:Carbolines; D007212:Indolizines
chemical_list: D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D050684:E2F Transcription Factors; D005947:Glucose; D007211:Indoles; D011484:Protein-Arginine N-Methyltransferases; D034741:RNA, Small Interfering; D056286:Retinoblastoma Binding Proteins; D044767:Ubiquitin-Protein Ligases; C000614131:CDKN2A protein, human; C000606393:RB1 protein, human; C069346:fascaplysine; D000644:Quaternary Ammonium Compounds; D002243:Carbolines; D007212:Indolizines; C400529:PRMT5 protein, human; C495900:CDK4 protein, human
keywords: PRMT5; cell cycle progression; competitive binding; glucose; hepatocellular carcinoma