title: Destabilization of Fatty Acid Synthase by Acetylation Inhibits De Novo Lipogenesis and Tumor Cell Growth.
abstract: Fatty acid synthase (FASN) is the terminal enzyme in de novo lipogenesis and plays a key role in cell proliferation. Pharmacologic inhibitors of FASN are being evaluated in clinical trials for treatment of cancer, obesity, and other diseases. Here, we report a previously unknown mechanism of FASN regulation involving its acetylation by KAT8 and its deacetylation by HDAC3. FASN acetylation promoted its degradation via the ubiquitin-proteasome pathway. FASN acetylation enhanced its association with the E3 ubiquitin ligase TRIM21. Acetylation destabilized FASN and resulted in decreased de novo lipogenesis and tumor cell growth. FASN acetylation was frequently reduced in human hepatocellular carcinoma samples, which correlated with increased HDAC3 expression and FASN protein levels. Our results suggest opportunities to target FASN acetylation as an anticancer strategy. Cancer Res; 76(23); 6924-36. ©2016 AACR.
authors.affiliation: Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.|Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.|State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Huai-Peng
authors.initials: HP
authors.lastname: Lin
authors.affiliation: Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.|Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.|State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Zhou-Li
authors.initials: ZL
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Surface Physics and Department of Physics, Fudan University, Shanghai, China.
authors.forename: Ruo-Yu
authors.initials: RY
authors.lastname: He
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, National Center for National Center for Protein Science (The PHOENIX Center), Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.|Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
authors.forename: Meng-Xin
authors.initials: MX
authors.lastname: Tian
authors.affiliation: Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.|Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.|State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Li-Sha
authors.initials: LS
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Beezly S
authors.initials: BS
authors.lastname: Groh
authors.affiliation: Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.|Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
authors.forename: Wei-Ren
authors.initials: WR
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Surface Physics and Department of Physics, Fudan University, Shanghai, China.
authors.forename: Min-Biao
authors.initials: MB
authors.lastname: Ji
authors.affiliation: Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.|Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.|State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.|State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, National Center for National Center for Protein Science (The PHOENIX Center), Beijing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Ding
authors.affiliation: Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.|Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Shi
authors.affiliation: Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China. kuguan@ucsd.edu yedan@fudan.edu.cn yxiong@email.unc.edu.|Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.|State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.|Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California.
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
authors.affiliation: Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China. kuguan@ucsd.edu yedan@fudan.edu.cn yxiong@email.unc.edu.|Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.|State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.|Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Ye
authors.affiliation: Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China. kuguan@ucsd.edu yedan@fudan.edu.cn yxiong@email.unc.edu.|Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.|State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.|Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong
mesh_terms: D000107:Acetylation; D048708:Cell Growth Processes / Q000235:genetics*; D049109:Cell Proliferation; D064429:Fatty Acid Synthases / Q000235:genetics*; D006801:Humans; D050155:Lipogenesis / Q000235:genetics*; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: D064429:Fatty Acid Synthases