Journal
ONCOTARGET
Volume 5, Issue 17, Pages 7303-7315Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2371
Keywords
acetylation; peroxisome proliferator-activated receptor gamma (Ppar gamma); nuclear receptors; silent mating type information regulation 2 homolog 1 (SIRT1); lipogenesis
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Funding
- Ellison Medical Foundation New Scholar Award in Aging
- NIH Cancer Center Core Grant [P30CA56036]
- Dr. Ralph and Marian C. Falk Medical Research Trust
- Pennsylvania Department of Health
- [R01CA70896]
- [R01CA75503]
- [R01CA86072]
- [RO1 DK073466]
- [K08DK094968]
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In our prior publications we characterized a conserved acetylation motif (K(R) xxKK) of evolutionarily related nuclear receptors. Recent reports showed that peroxisome proliferator activated receptor gamma (PPAR gamma) deacetylation by SIRT1 is involved in delaying cellular senescence and maintaining the brown remodeling of white adipose tissue. However, it still remains unknown whether lysyl residues 154 and 155 (K154/155) of the conserved acetylation motif (RIHKK) in Ppar gamma 1 are acetylated. Herein, we demonstrate that Ppar gamma 1 is acetylated and regulated by both endogenous TSA-sensitive and NAD-dependent deacetylases. Acetylation of lysine 154 was identified by mass spectrometry (MS) while deacetylation of lysine 155 by SIRT1 was confirmed by in vitro deacetylation assay. An in vivo labeling assay revealed K154/K155 as bona fide acetylation sites. The conserved acetylation sites of Ppar gamma 1 and the catalytic domain of SIRT1 are both required for the interaction between Ppar gamma 1 and SIRT1. Sirt1 and Ppar gamma 1 converge to govern lipid metabolism in vivo. Acetylation-defective mutants of Ppar gamma 1 were associated with reduced lipid synthesis in ErbB2 overexpressing breast cancer cells. Together, these results suggest that the conserved lysyl residues K154/K155 of Ppar gamma 1 are acetylated and play an important role in lipid synthesis in ErbB2-positive breast cancer cells.
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