Xiaoming Liu1,2, Jianye Liu3, Wen Xiao4, Qinghai Zeng5, Hao Bo6, Yuxing Zhu1, Lian Gong1, Dong He7, Xiaowei Xing8, Ruhong Li9, Ming Zhou6, Wei Xiong6, Yanhong Zhou6, Jianda Zhou10, Xiaohui Li11,12, Fei Guo11,13, Canxia Xu2,14, Xiong Chen2,14, Xiaoyan Wang2,14, Fen Wang2,14, Qiang Wang15, Ke Cao1. 1. Department of Oncology, Third Xiangya Hospital of Central South University, Changsha, China. 2. Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha, China. 3. Department of Urology, Third Xiangya Hospital of Central South University, Changsha, China. 4. Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, CAS Center for Excellence in Molecular Cell Science, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. 5. Department of Dermatology, Third Xiangya Hospital of Central South University, Changsha, China. 6. Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Cancer Research Institute, Central South University, Changsha, China. 7. Department of Respiratory, The Second People's Hospital of Hunan Province, Changsha, China. 8. Center for Medical Experiments, Third Xiangya Hospital of Central South University, Changsha, China. 9. Yan'an Affiliated Hospital of Kunming Medical University, Kunming, China. 10. Department of Plastic Surgery, Third Xiangya Hospital of Central South University, Changsha, China. 11. Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha, China. 12. Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Central South University, Changsha, China. 13. Department of Clinical Pharmacology, Xiangya Hospital of Central South University, Changsha, China. 14. Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, China. 15. Department of Transplantation, Third Xiangya Hospital of Central South University, Changsha, China.
Abstract
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is associated with high malignancy rates. Recently, a known deacetylase silent information regulator 1 (SIRT1) was discovered in HCC, and its presence is positively correlated with malignancy and metastasis. N6 -methyladenosine (m6 A) is the most prominent modification, but the exact mechanisms on how SIRT1 regulates m6 A modification to induce hepatocarcinogenesis remain unclear. APPROACH AND RESULTS: Here we demonstrate that SIRT1 exerts an oncogenic role by down-regulating fat mass and obesity-associated protein (FTO), which is an m6 A demethylase. A crucial component of small ubiquitin-related modifiers (SUMOs) E3 ligase, RANBP2, is activated by SIRT1, and it is indispensable for FTO SUMOylation at Lysine (K)-216 site that promotes FTO degradation. Moreover, Guanine nucleotide-binding protein G (o) subunit alpha (GNAO1) is identified as m6 A downstream targets of FTO and tumor suppressor in HCC, and depletion of FTO by SIRT1 improves m6 A+ GNAO1 and down-regulates its mRNA expression. CONCLUSIONS: We demonstrate an important mechanism whereby SIRT1 destabilizes FTO, steering the m6 A+ of downstream molecules and subsequent mRNA expression in HCC tumorigenesis. Our findings uncover a target of SIRT1 for therapeutic agents to treat HCC.
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is associated with high malignancy rates. Recently, a known deacetylase silent information regulator 1 (SIRT1) was discovered in HCC, and its presence is positively correlated with malignancy and metastasis. N6 -methyladenosine (m6 A) is the most prominent modification, but the exact mechanisms on how SIRT1 regulates m6 A modification to induce hepatocarcinogenesis remain unclear. APPROACH AND RESULTS: Here we demonstrate that SIRT1 exerts an oncogenic role by down-regulating fat mass and obesity-associated protein (FTO), which is an m6 A demethylase. A crucial component of small ubiquitin-related modifiers (SUMOs) E3 ligase, RANBP2, is activated by SIRT1, and it is indispensable for FTO SUMOylation at Lysine (K)-216 site that promotes FTO degradation. Moreover, Guanine nucleotide-binding protein G (o) subunit alpha (GNAO1) is identified as m6 A downstream targets of FTO and tumor suppressor in HCC, and depletion of FTO by SIRT1 improves m6 A+ GNAO1 and down-regulates its mRNA expression. CONCLUSIONS: We demonstrate an important mechanism whereby SIRT1 destabilizes FTO, steering the m6 A+ of downstream molecules and subsequent mRNA expression in HCC tumorigenesis. Our findings uncover a target of SIRT1 for therapeutic agents to treat HCC.