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

Peroxisome proliferator-activated receptor gamma (PPAR&gamma
) has recently been revealed to regulate tumor microenvironments. In particular, genetic alterations of PPAR&gamma
found in various cancers have been reported to play important roles in tumorigenesis by affecting PPAR&gamma
transactivation. In this study, we found that helix H3 of the PPAR&gamma
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 PPAR&gamma
LBDs containing helix H3 mutations found in cancers. Interestingly, PPAR&gamma
Q286E found in bladder cancer induces a constitutively active conformation of PPAR&gamma
LBD and thus abnormal activation of PPAR&gamma
/RXR&alpha
pathway, which suggests tumorigenic roles of PPAR&gamma
in bladder cancer. In contrast, other helix H3 mutations found in various cancers impair ligand binding essential for transcriptional activity of PPAR&gamma
These data indicate that cancer-associated mutations clustered in helix H3 of PPAR&gamma
LBD exhibit differential effects in PPAR&gamma
mediated tumorigenesis and provide a basis for the development of new biomarkers targeting tumor microenvironments.