Acetylation Stabilizes ATP-Citrate Lyase to Promote Lipid Biosynthesis and Tumor Growth

• Published in: Molecular cell Vol. 51; no. 4; pp. 506 - 518
• Main Authors: Lin, Ruiting, Tao, Ren, Gao, Xue, Li, Tingting, Zhou, Xin, Guan, Kun-Liang, Xiong, Yue, Lei, Qun-Ying
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.08.2013
• Subjects: Acetylation; Animals; ATP Citrate (pro-S)-Lyase - chemistry; ATP Citrate (pro-S)-Lyase - genetics; ATP Citrate (pro-S)-Lyase - metabolism; biosynthesis; Blotting, Western; Calmodulin-Binding Proteins - genetics; Calmodulin-Binding Proteins - metabolism; cell growth; Cell Proliferation; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; fatty acids; Fatty Acids - metabolism; glucose; Humans; Immunoenzyme Techniques; lung neoplasms; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; lysine; Male; Mice; Mice, Nude; neoplasm cells; p300-CBP Transcription Factors - genetics; p300-CBP Transcription Factors - metabolism; Proteasome Endopeptidase Complex - metabolism; Protein Processing, Post-Translational; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Sirtuin 2 - genetics; Sirtuin 2 - metabolism; Tumor Cells, Cultured; Ubiquitin - metabolism; Ubiquitination
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2013.07.002

Increased fatty acid synthesis is required to meet the demand for membrane expansion of rapidly growing cells. ATP-citrate lyase (ACLY) is upregulated or activated in several types of cancer, and inhibition of ACLY arrests proliferation of cancer cells. Here we show that ACLY is acetylated at lysine residues 540, 546, and 554 (3K). Acetylation at these three lysine residues is stimulated by P300/calcium-binding protein (CBP)-associated factor (PCAF) acetyltransferase under high glucose and increases ACLY stability by blocking its ubiquitylation and degradation. Conversely, the protein deacetylase sirtuin 2 (SIRT2) deacetylates and destabilizes ACLY. Substitution of 3K abolishes ACLY ubiquitylation and promotes de novo lipid synthesis, cell proliferation, and tumor growth. Importantly, 3K acetylation of ACLY is increased in human lung cancers. Our study reveals a crosstalk between acetylation and ubiquitylation by competing for the same lysine residues in the regulation of fatty acid synthesis and cell growth in response to glucose. •Acetylation stabilizes ACLY•Lung cancer has increased ACLY acetylation