LncRNA PCAT1 activates AKT and NF-B signaling in castration-resistant prostate cancer by regulating the PHLPP/FKBP51/IKK complex

Abstract

In PTEN-deficient prostate cancers, AKT signaling May be activated upon suppression of androgen receptor signaling. Activation of AKT as well as NFB signaling involves a key regulatory protein complex containing PHLPP, FKBP51 and IKK. Here, we report a critical role of lncRNA PCAT1 in regulating the PHLPP/FKBP51/IKK complex and progression of castration-resistant prostate cancer (CRPC). Using database queries, bioinformatic analyses, as well as RIP and RNA pull-down assays, we discovered and validated that the lncRNA-PCAT1 perturbs the PHLPP/FKBP51/IKK complex and activates AKT and NF-B signaling. Expression of lncRNA-PCAT1 is positively linked to CRPC progression. PCAT1 binds directly to FKBP51, displacing PHLPP from the PHLPP/FKBP51/IKK complex, leading to activation of AKT and NF-B signaling. Targeting PCAT1 restores PHLPP binding to FKBP1 leading to suppression of AKT signaling. Preclinical study in a mouse model of CRPC suggests therapeutic potential by targeting lncRNA PCAT1 to suppress CRPC progression. Together, the newly identified PCAT1/FKBP51/IKK complex provides mechanistic insight in the interplay between AKT, NF-B and AR signaling in CRPC, and the preclinical studies suggest that a novel role for PCAT1 as a therapeutic target.