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

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

Research output: Journal article publicationJournal articleAcademic researchpeer-review

25 Citations (Scopus)

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. RAS/RAF/MEK/ERK pathway signaling is known to be frequently activated in cancers, in which it regulates cell growth, malignant transformation, drug resistance, and stemness. Using hepatocellular carcinoma as a model system, Chan et al. describe a mechanism by which this oncogenic signaling pathway is regulated by PRMT6 at the post-translational level via arginine methylation.

Original languageEnglish
Pages (from-to)690-701.e8
JournalCell Reports
Volume25
Issue number3
DOIs
Publication statusPublished - 16 Oct 2018

Keywords

  • arginine methylation
  • cancer stemness
  • epigenetics
  • HCC
  • tumor-initiating cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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