Destabilization of Fatty Acid Synthase by Acetylation Inhibits <i>De Novo</i> Lipogenesis and Tumor Cell Growth

Huai-Peng Lin(Shanghai Medical College of Fudan University), Zhou‐Li Cheng(Shanghai Medical College of Fudan University), Ruo-Yu He(Fudan University), Lei Song(Beijing Proteome Research Center), Meng‐Xin Tian(Fudan University), Li-Sha Zhou(Shanghai Medical College of Fudan University), Beezly S. Groh(University of North Carolina at Chapel Hill), Wei‐Ren Liu(Fudan University), Minbiao Ji(Fudan University), Chen Ding(Shanghai Medical College of Fudan University), Ying-Hong Shi(Fudan University), Kun‐Liang Guan(Shanghai Medical College of Fudan University), Dan Ye(Shanghai Medical College of Fudan University), Yue Xiong(University of North Carolina at Chapel Hill)
Cancer Research
October 11, 2016
10.1158/0008-5472.can-16-1597
Cited by 154Open Access
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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.

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