2. Academic Validation
  3. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth

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.
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

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.
PMID: 23932781 DOI: 10.1016/j.molcel.2013.07.002
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.

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