title: SIRT1 regulates YAP2-mediated cell proliferation and chemoresistance in hepatocellular carcinoma.
abstract: The MST/YAP (mammalian Ste20-like kinase/Yes-associated protein 2) pathway plays an important role in hepatocellular carcinoma (HCC). Although post-translational modification-especially MST/Lats (large tumor suppressor)-mediated phosphorylation and PP1 (protein phosphatase-1)-mediated dephosphorylation-has been found to regulate the activity of YAP2, very little is known about its acetylation. In our experiments, we observed that the expression of SIRT1 is significantly upregulated in the tumor samples of the hepatocarcinoma patients, and SIRT1 mRNA level positively correlates with connective tissue growth factor (CTGF) mRNA level. We then found that SIRT1 deacetylates YAP2 protein in HCC cells and SIRT1-mediated deacetylation increases the YAP2/TEAD4 association, leading to YAP2/TEAD4 transcriptional activation and upregulated cell growth in HCC cells. Moreover, knockdown of SIRT1 blocks the cisplatin (CDDP)-induced nuclear translocation of YAP2 and enhances the chemosensitivity of HCC cells to CDDP treatment. Together, our findings reveal a new regulatory mechanism of YAP2 by the SIRT1-mediated deacetylation that may be involved in HCC tumorigenesis and drug resistance.
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: B
authors.initials: B
authors.lastname: Mao
authors.affiliation: Department of Orthopedics, Tianjin Hospital, Tianjin, China.
authors.forename: F
authors.initials: F
authors.lastname: Hu
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: P
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, Clinical Division of Surgery, Chinese PLA General Hospital, Beijing, China.
authors.forename: M
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Orthopedics, Clinical Division of Surgery, Chinese PLA General Hospital, Beijing, China.
authors.forename: F
authors.initials: F
authors.lastname: Yuan
authors.affiliation: 1] Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China [2] The Chinese Hippo Consortium, China.
authors.forename: S
authors.initials: S
authors.lastname: Meng
authors.affiliation: Department of Orthopedics, Clinical Division of Surgery, Chinese PLA General Hospital, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1] Institute of Biophysics, Chinese Academy of Sciences, Beijing, China [2] The Chinese Hippo Consortium, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Orthopedics, Clinical Division of Surgery, Chinese PLA General Hospital, Beijing, China.
authors.forename: W
authors.initials: W
authors.lastname: Bi
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D010750:Phosphoproteins / Q000502:physiology*; D056564:Sirtuin 1 / Q000502:physiology*; D014157:Transcription Factors; D015533:Transcriptional Activation; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D002945:Cisplatin