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PRMT6 Regulates RAS/RAF Binding and MEK/ERK-Mediated Cancer Stemness Activities in Hepatocellular Carcinoma through CRAF Methylation.
Chan, Lok Hei; Zhou, Lei; Ng, Kai Yu; Wong, Tin Lok; Lee, Terence K; Sharma, Rakesh; Loong, Jane H; Ching, Yick Pang; Yuan, Yun-Fei; Xie, Dan; Lo, Chung Mau; Man, Kwan; Artegiani, Benedetta; Clevers, Hans; Yan, Helen H; Leung, Suet Yi; Richard, Stéphane; Guan, Xin-Yuan; Huen, Michael S Y; Ma, Stephanie.
Afiliación
  • Chan LH; School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China.
  • Zhou L; School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China.
  • Ng KY; School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China.
  • Wong TL; School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China.
  • Lee TK; Department of Applied Biology & Chemical Technology, Hong Kong Polytechnic University, Hong Kong, China.
  • Sharma R; Proteomics & Metabolomics Core Facility, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China.
  • Loong JH; School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China.
  • Ching YP; School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China; State Key Laboratory for Liver Research, University of Hong Kong, Pokfulam, Hong Kong, China.
  • Yuan YF; State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Centre, Guangzhou, China.
  • Xie D; State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Centre, Guangzhou, China.
  • Lo CM; State Key Laboratory for Liver Research, University of Hong Kong, Pokfulam, Hong Kong, China; Department of Surgery, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China.
  • Man K; State Key Laboratory for Liver Research, University of Hong Kong, Pokfulam, Hong Kong, China; Department of Surgery, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China.
  • Artegiani B; Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Utrecht, the Netherlands.
  • Clevers H; Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Utrecht, the Netherlands.
  • Yan HH; Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China.
  • Leung SY; Department of Pathology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China.
  • Richard S; Lady Davis Institute, Jewish General Hospital, and Departments of Oncology and Medicine, McGill University, Montreal, QC, Canada.
  • Guan XY; State Key Laboratory for Liver Research, University of Hong Kong, Pokfulam, Hong Kong, China; Department of Clinical Oncology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China.
  • Huen MSY; School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China.
  • Ma S; School of Biomedical Sciences, University of Hong Kong, Pokfulam, Hong Kong, China; State Key Laboratory for Liver Research, University of Hong Kong, Pokfulam, Hong Kong, China. Electronic address: stefma@hku.hk.
Cell Rep ; 25(3): 690-701.e8, 2018 10 16.
Article en En | MEDLINE | ID: mdl-30332648
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína-Arginina N-Metiltransferasas / Células Madre Neoplásicas / Proteínas Nucleares / Regulación Neoplásica de la Expresión Génica / Carcinoma Hepatocelular / Metilación de ADN / Factor 3 Asociado a Receptor de TNF Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Cell Rep Año: 2018 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína-Arginina N-Metiltransferasas / Células Madre Neoplásicas / Proteínas Nucleares / Regulación Neoplásica de la Expresión Génica / Carcinoma Hepatocelular / Metilación de ADN / Factor 3 Asociado a Receptor de TNF Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Cell Rep Año: 2018 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos