AKT1 Regulates UHRF1 Protein Stability and Promotes the Resistance to Abiraterone in Prostate Cancer

Abstract

Abstract Oncogenic activation of PI3K/AKT signaling pathway, together with epigenetic aberrations is the characters of castration-resistant prostate cancer(CRPC). UHRF1 as a key epigenetic regulator, plays a critical role in prostate cancer (PCa) development, and its expression is closely associated with tumor malignancy. This present study investigated the potential regulatory relationship between AKT1 and UHRF1, and further validated the in vitro and in vivo anti-PCa efficacy of AKT phosphorylation inhibitor MK2206 in combination with abiraterone. Both UHRF1 and p-AKT aberrantly overexpressed in the abiraterone-resistant PCa cells. Further studies revealed that AKT1 protein interacts UHRF1, and AKT1 directly phosphorylates UHRF1 via the site Thr 210. MK2206 induced UHRF1 protein degradation by disrupting AKT1-induced UHRF1 phosphorylation, and then reduced the interaction between UHRF1 and deubiquitinating enzyme USP7, while promoted the interaction between UHRF and E3 ubiquitin protein ligase (BTRC). MK2206 significantly promoted the sensitivity of abiraterone-refractory PCa cells and xenografts to abiraterone by downregulating the levels of UHRF1, and reversed the transdifferentiation of NEPC (SYP and NCAM1), even activated cell senescence (p21 upregulation) and cell apoptosis (cleaved-PARP). Altogether, our present study for the first time revealed a novel molecular mechanism of abiraterone resistance through PI3/AKT-UHRF1 pathway, and provided a novel therapeutic modality by targeting PI3/AKT1 to promote the drug sensitivity of abiraterone in PCa patients.