Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth.
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.
Key Laboratory of Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Shanghai 200032, China.|Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Shanghai 200032, China.|School of Life Science Fudan University, Shanghai 200032, China.
Ruiting
R
Lin
Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong New Area, Shanghai 200120, China.
Ren
R
Tao
Key Laboratory of Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Shanghai 200032, China.|Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Shanghai 200032, China.|School of Life Science Fudan University, Shanghai 200032, China.
Xue
X
Gao
Key Laboratory of Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Shanghai 200032, China.|Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Shanghai 200032, China.|School of Life Science Fudan University, Shanghai 200032, China.
Tingting
T
Li
Key Laboratory of Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Shanghai 200032, China.|Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Shanghai 200032, China.|School of Life Science Fudan University, Shanghai 200032, China.
Xin
X
Zhou
Key Laboratory of Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Shanghai 200032, China.|Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Shanghai 200032, China.|Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92037-0695, USA.
Kun-Liang
KL
Guan
Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Shanghai 200032, China.|School of Life Science Fudan University, Shanghai 200032, China.|Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Yue
Y
Xiong
Key Laboratory of Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Shanghai 200032, China.|Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Shanghai 200032, China.
Qun-Ying
QY
Lei
D001275:ATP Citrate (pro-S)-Lyase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
D001275:ATP Citrate (pro-S)-Lyase; D002148:Calmodulin-Binding Proteins; D003598:Cytoskeletal Proteins; D005227:Fatty Acids; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger; D056565:Sirtuin 2; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C505833:UBR4 protein, human; C474199:SIRT2 protein, human