Abstract
Simple SummaryThe high frequency of mutations in helix H3 of the peroxisome proliferator-activated receptor gamma (PPARγ) ligand-binding domain (LBD) in various cancers suggest that this region has an important role in tumorigenesis. In this study, we performed bioinformatics, structural and biochemical analyses to characterize PPARγ LBDs with helix H3 mutations found in cancers. In the absence of ligands, PPARγ Q286E that was a mutation found in patients with bladder cancer induced a constitutively active conformation of PPARγ and promoted coactivator recruitment, providing evidence for tumorigenic effects. A number of other mutations reduced PPARγ activation by various mechanisms. Accordingly, mutations in helix H3 of PPARγ LBD have a wide range of effects and are key candidates for the development of biomarkers and targeted therapies.Peroxisome proliferator-activated receptor gamma (PPARγ) has recently been revealed to regulate tumor microenvironments. In particular, genetic alterations of PPARγ found in various cancers have been reported to play important roles in tumorigenesis by affecting PPARγ transactivation. In this study, we found that helix H3 of the PPARγ ligand-binding domain (LBD) has a number of sites that are mutated in cancers. To uncover underlying molecular mechanisms between helix H3 mutations and tumorigenesis, we performed structure‒function studies on the PPARγ LBDs containing helix H3 mutations found in cancers. Interestingly, PPARγ Q286E found in bladder cancer induces a constitutively active conformation of PPARγ LBD and thus abnormal activation of PPARγ/RXRα pathway, which suggests tumorigenic roles of PPARγ in bladder cancer. In contrast, other helix H3 mutations found in various cancers impair ligand binding essential for transcriptional activity of PPARγ. These data indicate that cancer-associated mutations clustered in helix H3 of PPARγ LBD exhibit differential effects in PPARγ-mediated tumorigenesis and provide a basis for the development of new biomarkers targeting tumor microenvironments.
Highlights
Peroxisome proliferator-activated receptor gamma (PPARγ) belonging to thyroid hormone receptor-like nuclear receptor subfamily 1 is a ligand-inducible transcription factor [1]
We found that helix H3 of PPARγ ligand-binding domain (LBD) is enriched for mutations that are found in cancers; helix H3 accounts for only 9.4% of the amino acids in the PPARγ LBD but 19.6% of
Because it might provide insight into the mechanisms underlying PPARγ-mediated tumorigenesis, we focused on mutations in helix H3 of PPARγ LBD for further structure–function analyses
Summary
Peroxisome proliferator-activated receptor gamma (PPARγ) belonging to thyroid hormone receptor-like nuclear receptor subfamily 1 is a ligand-inducible transcription factor [1]. PPARγ full agonist thiazolidinedione (TZD) drugs, such as pioglitazone and rosiglitazone, have been widely used for the treatment of diabetes, despite known side effects, such as weight gain, fluid retention and bone loss [6,7,8]. Activation of PPARγ by agonists exerts inhibitory effects on tumor growth by various mechanisms, including apoptosis, cell cycle arrest and inhibitions of angiogenesis or differentiation [12,13,14,15]. TZD drugs elicit tumor-suppressive effects to induce apoptosis and inhibit cell proliferation in various cancer cells by regulating apoptosis-associated proteins, such as cyclooxygenase-2 (COX-2), B-cell lymphoma 2 (Bcl-2), epidermal growth factor receptor (EGFR) and Fas ligand (FasL) [18,19,20,21,22]. There have been clinical trials for various cancers using PPARγ agonists such as pioglitazone [23]
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