PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Stemness Activities in Hepatocellular Carcinoma through CRAF Methylation.

Abstract

Arginine methylation is a post-translational modification that plays pivotal roles in signal transduction and gene transcription during cell fate determination. We found protein methyltransferase 6 (PRMT6) to be frequently downregulated in hepatocellular carcinoma (HCC) and its expression to negatively correlate with aggressive cancer features in HCC patients. Silencing of PRMT6 promoted the tumor-initiating, metastasis, and therapy resistance potential of HCC cell lines and patient-derived organoids. Consistently, loss of PRMT6 expression aggravated liver tumorigenesis in a chemical-induced HCC PRMT6 knockout (PRMT6-/-) mouse model. Integrated transcriptome and protein-protein interaction studies revealed an enrichment of genes implicated in RAS signaling and showed that PRMT6 interacted with CRAF on arginine 100, which decreased its RAS binding potential and altered its downstream MEK/ERK signaling. Our work describes a critical repressive function for PRMT6 in maintenance of HCC cells by regulating RAS binding and MEK/ERK signaling via methylation of CRAF on arginine 100.

• Authors: Lok Hei Chan, Lei Zhou, Kai Yu Ng, Tin Lok Wong, Terence K Lee, Rakesh Sharma, Jane H Loong, Yick Pang Ching, Yun-Fei Yuan, Dan Xie, Chung Mau Lo, Kwan Man, Benedetta Artegiani, Hans Clevers, Helen H Yan, Suet Yi Leung, Stéphane Richard, Xin-Yuan Guan, Michael S Y Huen, Stephanie Ma
• Journal: Cell reports (Cell Rep) Vol. 25 Issue 3 Pg. 690-701.e8 (10 16 2018) ISSN: 2211-1247 [Electronic] United States
• PMID: 30332648 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Nuclear Proteins
• TNF Receptor-Associated Factor 3
• PRMT6 protein, human
• PRMT6 protein, mouse
• Protein-Arginine N-Methyltransferases
• raf Kinases
• MAP Kinase Kinase 1
• ras Proteins

Topics

• Animals
• Apoptosis
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Cell Proliferation
• DNA Methylation
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms (genetics, metabolism, pathology)
• MAP Kinase Kinase 1 (genetics, metabolism)
• MAP Kinase Signaling System
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred NOD
• Mice, Knockout
• Mice, Nude
• Mice, SCID
• Neoplastic Stem Cells (metabolism, pathology)
• Nuclear Proteins (genetics, metabolism)
• Protein-Arginine N-Methyltransferases (genetics, metabolism, physiology)
• TNF Receptor-Associated Factor 3 (genetics)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• raf Kinases (genetics, metabolism)
• ras Proteins (genetics, metabolism)