MOF-mediated acetylation of SIRT6 disrupts SIRT6-FOXA2 interaction and represses SIRT6 tumor-suppressive function by upregulating ZEB2 in NSCLC
Kaiqiang Zhao,
Mingyue Zheng,
Zezhuo Su,
Shrestha Ghosh,
Chao Zhang,
Wenzhao Zhong,
Joshua Wing Kei Ho,
Guoxiang Jin,
Zhongjun Zhou
Affiliations
Kaiqiang Zhao
Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, P.R. China; School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, P.R. China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, P.R. China
Mingyue Zheng
Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, P.R. China
Zezhuo Su
School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, P.R. China; Laboratory of Data Discovery for Health Limited (D24H), Hong Kong Science Park, Hong Kong SAR, P.R. China
Shrestha Ghosh
School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, P.R. China; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
Chao Zhang
Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, P.R. China
Wenzhao Zhong
Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, P.R. China
Joshua Wing Kei Ho
School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, P.R. China; Laboratory of Data Discovery for Health Limited (D24H), Hong Kong Science Park, Hong Kong SAR, P.R. China
Guoxiang Jin
Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, P.R. China; Corresponding author
Zhongjun Zhou
Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, P.R. China; School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, P.R. China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, P.R. China; Reproductive Medical Center, The University of Hong Kong Shenzhen Hospital, Shenzhen, P.R. China; Corresponding author
Summary: Mammalian sirtuin 6 (SIRT6) regulates a spectrum of vital biological processes and has long been implicated in the progression of cancer. However, the mechanisms underlying the regulation of SIRT6 in tumorigenesis remain elusive. Here, we report that the tumor-suppressive function of SIRT6 in non-small cell lung cancer (NSCLC) is regulated by acetylation. Specifically, males absent on the first (MOF) acetylates SIRT6 at K128, K160, and K267, resulting in a decreased deacetylase activity of SIRT6 and attenuated SIRT6 tumor-suppressive function in NSCLC. Mechanistically, MOF-mediated SIRT6 acetylation hinders the interaction between SIRT6 and transcriptional factor FOXA2, which in turn leads to the transcriptional activation of ZEB2, thus promoting NSCLC progression. Collectively, these data indicate an acetylation-dependent mechanism that modulates SIRT6 tumor-suppressive function in NSCLC. Our findings suggest that the MOF-SIRT6-ZEB2 axis may represent a promising therapeutic target for the management of NSCLC.
