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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263175 | GEO | 2025/09/17

REPOSITORIES: GEO

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Project description:Rosiglitazone (Rosi), a member of the thiazolidinedione class of drugs used to treat type 2 diabetes, activates the adipocyte-specific transcription factor peroxisome proliferator-activated receptor gamma (PPARg). This activation causes bone loss in animals and humans, at least in part due to suppression of osteoblast differentiation from marrow mesenchymal stem cells (MSC). In order to identify mechanisms by which PPARg2 suppresses osteoblastogenesis and promotes adipogenesis in MSC, we have analyzed the PPARg2 transcriptome in response to Rosi. A total of 4,252 transcriptional changes resulted when Rosi (1 uM) was applied to the U-33 marrow stromal cell line, stably transfected with PPARg2 (U-33/g2), as compared to non-induced U-33/g2 cells. Differences between U-33/g2 and U-33 cells stably transfected with empty vector (U-33/c) comprised 7,928 transcriptional changes, independent of Rosi. Cell type-, time- and treatment-specific gene clustering uncovered distinct patterns of PPARg2 transcriptional control of MSC lineage commitment. The earliest changes accompanying Rosi activation of PPARg2 included adjustments in morphogenesis, Wnt signaling, and immune responses, as well as sustained induction of lipid metabolism. Expression signatures influenced by longer exposure to Rosi provided evidence for distinct mechanisms governing the repression of osteogenesis and stimulation of adipogenesis. Our results suggest interactions that could lead to the identification of a “master” regulatory scheme controlling osteoblast differentiation. Keywords: rosiglitazone, PPARgamma, microarray, time course, gene expression, stem cells U-33/g2 and U-33/c cells were cultured in the presence or absence of Rosi and gene expression was monitored at three different time points (2, 24, 72h) after exposure to the agonist. Each time point corresponds to a separate stage of Rosi-treated U-33/g2 cell conversion from the osteoblast-like phenotype to the adipocyte-like phenotype and includes induction (2h), intermediate alterations in phenotype progression (24h), and a terminally differentiated adipocytic with completely suppressed osteoblastic phenotype (72h). The experiment is a full factorial design performed in replicate.

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

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