PLAGL2 promotes bladder cancer progression via RACGAP1/RhoA GTPase/YAP1 signaling

Abstract

AbstractPLAGL2 is upregulated in various tumors, including bladder cancer (BCa). However, the mechanisms underlying the tumorigenic effects of PLAGL2 in BCa remain unclear. In our study, we proved that PLAGL2 was overexpressed in BCa tissues and correlated with decreased survival. Functionally, PLAGL2 deficiency significantly suppressed the proliferation and metastasis of BCa cells in vitro and in vivo. RNA sequencing, qRT‒PCR, immunoblotting, immunofluorescence staining, luciferase reporter, and ChIP assays revealed that overexpressed PLAGL2 disrupted the Hippo pathway and increased YAP1/TAZ activity by transactivating RACGAP1. Further investigations demonstrated that PLAGL2 activated YAP1/TAZ signaling via RACGAP1-mediated RhoA activation. Importantly, the RhoA inhibitor simvastatin or the YAP1/TAZ inhibitor verteporfin abrogated the proproliferative and prometastatic effects of BCa enhanced by PLAGL2. These findings suggest that PLAGL2 promotes BCa progression via RACGAP1/RhoA GTPase/YAP1 signaling. Hence, the core nodes of signaling may be promising therapeutic targets for BCa.