EGFR/MDM2 Signaling Promotes NFκB Activation Via PPARγ Degradation

Epidermal growth factor receptor(EGFR) signal is involved in cell proliferation,migration, adhesion, metastasis, and dysregulated EGFR expression has been implicated in cancers of the colon, lung, brain, breast, and pancreas, while peroxisome proliferator-activated receptor γ(PPARγ) negatively regulates cancer progression. Our previous study shows that PPARγ acts as an E3 ubiquitin ligase to induce NFκB/p65 ubiquitination and degradation, leading to inhibition of cell pro-inflammation and tumor growth. However, the molecular mechanism of EGFR interaction with PPARγis still unclear. Here we revealed a novel mechanism of EGFR/NFκB signaling promoted tumor cell prolefeartion by destructing PPARγ. The significant findings were below.1. PPARγ is a target of nuclear EGFR, which in turn induced nuclear PPARγ-Y74phosphorylation.2. Nuclear EGFR-mediated PPARγ phosphorylation recruited MDM2 ubiquitin ligasetoward PPARγ resulting in its ubiquitination and degradation.3. EGFR-mediated PPARγ degradation led to promotion of EGFR/NFκBsignaling-mediated cell proliferation, survival, chemoresistance. In contrast,PPARγ-Y74 mutant reversed this event. Moreover, PPARγ-Y74 A mutantsuppressed cell proliferation and increased chemotherapeutic agents-induced cancercell sensitivity.4. The clinical findings show that the nuclear phosphorylation of PPARγ-Y74 andEGFR expression in colonic cancer tissues was higher than that in control normaltissues.