PPARg acetylation governs mammary adenocarcinoma tumor growth via acetylated residues that determine DNA sequence-specific binding

Peroxisome proliferator-activated receptorg (PPARg), which is expressed in a variety of malignancies, governs biological functions through transcriptional programs. Defining the molecular mechanisms governing selection of canonical versus non-canonical PPARg binding sequences may provide the opportunity to design regulators with distinct functions and side effects. PPARg is acetylated at multiple residues including K268/293 in mouse Pparg2 and the conserved lysine residues (K154/155) in mouse Pparg1. Herein, the PPARg acetylated residues K154/155 were shown to be essential for growth control, and the induction of transcriptional modules governing growth factor signaling, cellular apoptosis and autophagy. The K154/155 residues determined the selection of genome wide DNA binding sites, altering the selection from canonical to non-canonical (C/EBP) DNA sequence specific binding. The gene signature reflecting the acetylation-dependent genomic occupancy provided predictive value in patient survival outcome. Pparg1 participates in ErbB2-induced tumor growth and inflammation and represents a relevant target for therapeutic coextinction. Overall design: Chromatin immunoprecipitation DNA-sequencing (CHIP-Seq) was used to determine how PPARg K154/155Q acetylation deficeint mutant influences the binding of PPARg to genomic DNAs. The flag tagged wild PPARg and PPARg K154/155Q mutant were stable tranfected into NeuT transformed MCF10A cells respectively. Anti-flag IP were used to pull down wildtype PPARg or PPARg K154/155Q mutant bound DNA.