Differential Effects of Cancer-Associated Mutations Enriched in Helix H3 of PPARγ

Abstract

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.

PPARγ Targets-Derived Diagnostic and Prognostic Index for Papillary Thyroid Cancer

“…The LBD, situated in the C-terminus, is connected to the DNA-binding domain (DBD) via a flexible hinge region, which interacts physically with the DNA in PPARγ [11]. It is a key domain for transactivation and transrepression of PPARγ target genes that play important roles in adipogenesis, insulin sensitization, lipid metabolism, and inflammation, making PPARγ an effective target for the management of metabolic diseases, such as type 2 diabetes, obesity, and atherosclerosis [22,45]. The PPARG gene has 15 transcripts (splice variants), of which four transcripts lack exon 5 and 6, which encode LBD (Figure S3A).…”

“…In cancer, the tumorigenic role of PPARγ remains highly controversial. Studies have observed the inhibitory effects of PPARγ-RXRα signaling pathway on tumor growth, angiogenesis, differentiation, and that of production of inflammatory cytokines and tumor invasiveness, suggesting the anti-tumorigenic role of PPARγ in several cancer types including colon, lung, pancreas, prostate, and breast cancer [11,45]. By contrast, the protumorigenic role of PPARγ has been reported in a variety of cancers, such as bladder tumor, renal pelvic tumors, hemangioma, lipoma, skin fibrosarcoma, mammary adenocarcinoma, and hepatic tumors, through distinct molecular mechanisms activated by PPARγ ligands regulating cancer cell proliferation, angiogenesis, and metastasis [46].…”