Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth

Ruiting Lin; Ren Tao; Xue Gao; Tingting Li; Xin Zhou; Kun-Liang Guan; Yue Xiong; Qun-Ying Lei

doi:10.1016/j.molcel.2013.07.002

Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth

Mol Cell. 2013 Aug 22;51(4):506-518. doi: 10.1016/j.molcel.2013.07.002. Epub 2013 Aug 8.

Authors

Ruiting Lin^#^{1

2

3}, Ren Tao^#⁴, Xue Gao^{1

2

3}, Tingting Li^{1

2

3}, Xin Zhou^{1

2

3}, Kun-Liang Guan^{1

2

5}, Yue Xiong^{2

3

6}, Qun-Ying Lei^{1

2}

Affiliations

¹ 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.
² Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Shanghai 200032, China.
³ School of Life Science Fudan University, Shanghai 200032, China.
⁴ Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong New Area, Shanghai 200120, China.
⁵ Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92037-0695, USA.
⁶ Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

^# Contributed equally.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

ATP Citrate (pro-S)-Lyase / chemistry*
ATP Citrate (pro-S)-Lyase / genetics
ATP Citrate (pro-S)-Lyase / metabolism*
Acetylation
Animals
Blotting, Western
Calmodulin-Binding Proteins / genetics
Calmodulin-Binding Proteins / metabolism
Cell Proliferation*
Cytoskeletal Proteins / genetics
Cytoskeletal Proteins / metabolism
Fatty Acids / metabolism*
Humans
Immunoenzyme Techniques
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / pathology*
Male
Mice
Mice, Nude
Proteasome Endopeptidase Complex / metabolism
Protein Processing, Post-Translational
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Sirtuin 2 / genetics
Sirtuin 2 / metabolism
Tumor Cells, Cultured
Ubiquitin / metabolism
Ubiquitin-Protein Ligases
Ubiquitination
p300-CBP Transcription Factors / genetics
p300-CBP Transcription Factors / metabolism

Substances

Calmodulin-Binding Proteins
Cytoskeletal Proteins
Fatty Acids
RNA, Messenger
Ubiquitin
p300-CBP Transcription Factors
p300-CBP-associated factor
UBR4 protein, human
Ubiquitin-Protein Ligases
ATP Citrate (pro-S)-Lyase
Proteasome Endopeptidase Complex
SIRT2 protein, human
Sirtuin 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding