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: Liu Liu, Xiaoping Zhao, Li Zhao, Jiajin Li, Hao Yang, Zongping Zhu, Jianjun Liu, Gang Huang
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 5 Pg. 1260-72 (Mar 01 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 26759235 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Sterol Regulatory Element Binding Protein 1
• Arginine
• PRMT5 protein, human
• Protein-Arginine N-Methyltransferases

Topics

• Arginine (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Humans
• Lipogenesis
• Liver Neoplasms (pathology)
• Methylation
• Phosphorylation
• Protein Stability
• Protein-Arginine N-Methyltransferases (physiology)
• Sterol Regulatory Element Binding Protein 1 (chemistry, metabolism)
• Xenograft Model Antitumor Assays