PPARγ is a tumor suppressor in basal bladder tumors offering new potential therapeutic opportunities - Archive ouverte HAL Accéder directement au contenu
Pré-Publication, Document De Travail Année : 2021

PPARγ is a tumor suppressor in basal bladder tumors offering new potential therapeutic opportunities

Hélène Neyret-Kahn
Florent Dufour
Elodie Chapeaublanc
François Radvanyi

Résumé

PPARactivation is a critical event in luminal muscle-invasive bladder cancer (MIBC) tumorigenesis, favoring both tumor cell growth and microenvironment modulation toward tumor immune escape. Conversely, the down-regulation of PPARactivity in basal MIBC suggests tumor suppressive effects in this subgroup. Here, we report genetic, epigenetic and functional evidence to support the tumor suppressor role for PPAR in basal bladder tumors. We identified hemizygous deletions, DNA hyper-methylation and loss-of-function mutations of PPARin basal MIBC, associated with PPAR under-expression and its decreased activity. Re-expression of PPARin basal tumor cells resulted in the activation of PPAR-dependent transcription program that modulated fatty acid metabolism and cell differentiation and decreased cell growth, which could partly rely on EGFR down-regulation. Structure-function studies of two PPAR mutant revealed a destabilization of a region important for coactivator recruitment and should help develop potent molecules to activate PPAR as a therapeutic strategy for basal MIBC. The identification of this subtype-dependent dual role of PPAR in MIBC strengthens the critical role of PPAR in bladder tumorigenesis and reinforces the interest in stratified medicine based on tumor molecular subtyping.
Fichier principal
Vignette du fichier
Biorxivversion.pdf (6.03 Mo) Télécharger le fichier
Origine Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03424976 , version 1 (16-11-2021)

Identifiants

Citer

Laure Coutos-Thévenot, Syrine Beji, Hélène Neyret-Kahn, Quentin Pippo, Jacqueline Fontugne, et al.. PPARγ is a tumor suppressor in basal bladder tumors offering new potential therapeutic opportunities. 2021. ⟨hal-03424976⟩
68 Consultations
64 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More