Abstract 5176: PPARγ acetylation governs differentiation function.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The peroxisome proliferator-activator receptor gamma (PPARγ) is a member of nuclear receptors (NRs) that plays an important role in the pathogenesis of human diseases, including obesity, type II diabetes and cancer. PPARγ regulates lipid homeostasis by activating the transcription of key genes that are responsible for lipid biosynthesis. NRs undergo post-translational modification including phosphorylation and acetylation. Direct nuclear receptor acetylation by histone acetyltransferases regulates ligand sensitivity and growth properties. Using mass spectrometry and in vivo labeling assays we showed that PPARγ is acetylated in cultured cells. Inhibition of endogenous TSA-sensitive and NAD-dependent deacetylase activity enhanced Pparγ acetylation. SIRT1 bound and deacetylated Pparγ at K154/155. These lysine residues of Pparγ were required for adipocyte differentiation function and determined distinct gene expression signaling pathways. The lysine residues governing sumoylation (K77) and acetylation (K154/155) were shown to have dissociable functions in regulating cell-cycle, gene expression, gene promoter activity, and protein stability. Breast tumor growth, de novo lipid synthesis, induction of autophagy and evasion of apoptosis was promoted by K154/155 and inhibited by K77 in vivo. Pparγ acetylation induced a gene signature that was increased in breast cancer, associated with a reduction in SIRT1 abundance and poor outcome. These studies suggest that the Pparγ lysine motif regulates both ligand-dependent receptor stability and receptor-dependent gene expression and cell functions. Pparγ and SIRT1 signaling converge in vivo to regulate breast tumor lipid metabolism and growth. Citation Format: Lifeng Tian, Chenguang Wang, Fred K. Hagen, Mathew Casimiro, Anthony A. Sauve, Richard G. Pestell. PPARγ acetylation governs differentiation function. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5176. doi:10.1158/1538-7445.AM2013-5176