Emerging role of the β-catenin-PPARγ axis in the pathogenesis of colorectal cancer

Figure 2 Schematic model of PPARγ signaling in epithelial cells. PPARγ acts as a pro-differentiating transcription factor in colonic epithelial cells where it is abundantly expressed. A variety of endogenous and exogenous compounds, including lipophilic molecules such as polyunsaturated fatty acids and prostaglandines, have been identified as PPARγ ligands; in particular, 15-deoxy-Δ12,14-PGJ2 (15dPGJ2), is considered a natural ligand for PPARγ. Two molecular mechanisms have been proposed to explain PPARγ effects in maintaining cellular differentiation and homeostasis referred to as PPARγ ligand-dependent or PPARγ ligand-independent effects. (1) in the ligand-dependent transactivation, PPARγ binds the cognate PPRE as heterodimer with RXR and activates target gene expression (PTEN, p21, CDH1) through the recruitment of coactivators; (2) an alternative mode of action is known as ligand-dependent trans-repression, in which the SUMOylated form of the receptor interacts with transcription factors such as NFκB, STAT or JUN and represses their target genes transcription. This is attained through the recruitment and stabilization of corepressor complexes at the promoter regions of proinflammatory or protumorigenic genes by a functionally distinct pool of PPARγ that is specifically SUMOylated at susceptible aminoacid residues in the presence of selected agonists.