title: Deacetylation of Ku70 by SIRT6 attenuates Bax-mediated apoptosis in hepatocellular carcinoma.
abstract: SIRT6 is a class III histone deacetylase that has been implicated in HCC development. We previously reported that SIRT6 potentiated apoptosis evasion in hepatocellular carcinoma by inhibiting both Bax expression and mitochondrial translocalization. However, the mechanism underlying SIRT6-mediated inhibition of Bax mitochondrial localization remains elusive. In this study, we found that although SIRT6 had no effect on the expression level of Ku70, SIRT6 could interact with Ku70 and deacetylate it. The increased acetylation of Ku70 in SIRT6-depleted cells disrupt its interaction with Bax, which finally resulted in Bax mitochondrial translocalization. Furthermore, lysine K542 on Ku70 was the target for deacetylation by SIRT6. Ku70K542Qmutation abolished suppression of association between Ku70 and Bax and caused redistribution of Bax to the cytosol in SIRT6-depleted cells. Finally, Ku70K542Qmutation could reversed the inhibition of growth and apoptosis promotion mediated by SIRT6 silencing. Together, our findings revealed SIRT6 could block the mitochondrial translocation of Bax and decrease the apoptotic ratio of HCC cells by deacetylation of Ku70. SIRT6 may serve as a promising target for developing targeted therapies for HCC in the future.
authors.affiliation: The Second Affiliated Hospital and the Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Tao
authors.affiliation: The Second Affiliated Hospital and the Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
authors.forename: Ji-Hua
authors.initials: JH
authors.lastname: Ren
authors.affiliation: The Second Affiliated Hospital and the Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Zhejiang, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Tang
authors.affiliation: Department of Anesthesiology, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Long-Kuan
authors.initials: LK
authors.lastname: Ran
authors.affiliation: The Second Affiliated Hospital and the Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
authors.forename: Hong-Zhong
authors.initials: HZ
authors.lastname: Zhou
authors.affiliation: The Second Affiliated Hospital and the Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: The Second Affiliated Hospital and the Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Zhejiang, China. Electronic address: ahuang1964@163.com.
authors.forename: Ai-Long
authors.initials: AL
authors.lastname: Huang
authors.affiliation: The Second Affiliated Hospital and the Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China. Electronic address: yixin_xinyuan@163.com.
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
mesh_terms: D000107:Acetylation; D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015870:Gene Expression; D006801:Humans; D000072200:Ku Autoantigen / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D021381:Protein Transport / Q000235:genetics; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051028:bcl-2-Associated X Protein; C516592:SIRT6 protein, human; D037761:Sirtuins; D000072200:Ku Autoantigen; D008239:Lysine
keywords: Apoptosis; Hepatocellular carcinoma; Ku70; SIRT6