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

Cell Rep. 2018 Oct 16;25(3):690-701.e8. doi: 10.1016/j.celrep.2018.09.053.


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.

Keywords: HCC; arginine methylation; cancer stemness; epigenetics; tumor-initiating cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • 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