title: Arginine Methylation of SREBP1a via PRMT5 Promotes De Novo Lipogenesis and Tumor Growth.
abstract: Dysregulation of the sterol regulatory element-binding transcription factors sterol regulatory element-binding protein (SREBP) and SREBF activates de novo lipogenesis to high levels in cancer cells, a critical event in driving malignant growth. In this study, we identified an important posttranslational mechanism by which SREBP1a is regulated during metabolic reprogramming in cancer cells. Mass spectrometry revealed protein arginine methyltransferase 5 (PRMT5) as a binding partner of SREBP1a that symmetrically dimethylated it on R321, thereby promoting transcriptional activity. Furthermore, PRMT5-induced methylation prevented phosphorylation of SREBP1a on S430 by GSK3β, leading to its disassociation from Fbw7 (FBXW7) and its evasion from degradation through the ubiquitin-proteasome pathway. Consequently, methylation-stabilized SREBP1a increased de novo lipogenesis and accelerated the growth of cancer cells in vivo and in vitro. Clinically, R321 symmetric dimethylation status was associated with malignant progression of human hepatocellular carcinoma, where it served as an independent risk factor of poor prognosis. By showing how PRMT5-induced methylation of SREBP1a triggers hyperactivation of lipid biosynthesis, a key event in tumorigenesis, our findings suggest a new generalized strategy to selectively attack tumor metabolism.
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jiajin
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zongping
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China. huanggang0311@163.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
mesh_terms: D001120:Arginine / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D050155:Lipogenesis; D008113:Liver Neoplasms / Q000473:pathology*; D008745:Methylation; D010766:Phosphorylation; D055550:Protein Stability; D011484:Protein-Arginine N-Methyltransferases / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000737:chemistry / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051780:Sterol Regulatory Element Binding Protein 1; D001120:Arginine; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases