AKT1 regulates UHRF1 protein stability and promotes the resistance to abiraterone in prostate cancer

Abstract

Oncogenic activation of PI3K/AKT signaling pathway, together with epigenetic aberrations are 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 positively correlated with the degree of malignancy. In this present study we investigated the potential regulatory mechanism of AKT1 on UHRF1, and further validated the in vitro and in vivo anticancer 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 with UHRF1, and AKT1 directly phosphorylates UHRF1 via the site Thr-210. MK2206 induced UHRF1 protein degradation by inhibiting AKT1-induced UHRF1 phosphorylation, and then reduced the interaction between UHRF1 and deubiquitinase USP7, while promoted the interaction between UHRF1 and E3 ubiquitin protein ligase BTRC. MK2206 significantly promoted the sensitivity of abiraterone-refractory PCa cells and xenografts to abiraterone by decreasing UHRF1 protein level, and reversed the phenotype of NEPC, evently induced cellular senescence and cell apoptosis. Altogether, our present study for the first time revealed a novel molecular mechanism of abiraterone resistance through PI3K/AKT-UHRF1 pathway, and provided a novel therapeutic modality by targeting PI3K/AKT1 to promote the drug sensitivity of abiraterone in PCa patients.

Identification of an anaplastic subtype of prostate cancer amenable to therapies targeting SP1 or translation elongation

“…S8F). Using a previously established pair of parental or Abi-refractory lines 22RV1/22RV1-R ( 46 ), we showed that 22RV1-R (versus parental AR-high 22RV1) exhibited a preferential sensitivity to SP1i (fig. S8G), highlighting an enhanced dependency of SP1 in CRPC cells.…”

Roles of post-translational modifications of UHRF1 in cancer

“…In addition to the regulatory roles in cell cycle, our laboratory has recently reported that AKT1 [ 31 ], by inducing the phosphorylation of threonine 210 of UHRF1, maintains the protein stability of UHRF1 (Fig. 1 ).…”

“…For example, AKT1-induced UHRF1 phosphorylation (UHRF1-T210) inhibits the ubiquitination of UHRF1. Phosphorylation of AKT1 promotes the USP7-induced deubiquitination of UHRF1, while concurrently inhibiting the SCFβ-TrCP-mediated protein ubiquitination of UHRF1, which leads to the resistance of PCa cells to abiraterone [ 31 ]. M phase-specific kinase CDK1/cyclin B induces the phosphorylation of UHRF1 at S652, thereby reducing the interaction between UHRF1 and USP7, redu c ing the USP7-mediated deubiquitination of UHRF1 and promoting protein degradation, consequently inhibiting cell proliferation [ 28 ].…”

H3 histone methylation landscape in male urogenital cancers: from molecular mechanisms to epigenetic biomarkers and therapeutic targets

“…Some AR inhibitors, such as enzalutamide and abiraterone (CYP17A1 inhibitor), have been approved by the FDA for the treatment of advanced stage PCa ( Rodriguez-Vida et al, 2015 ). However, some cases develop resistance to enzalutamide and abiraterone, making the disease almost incurable ( Wang and Liu, 2020 ; Fu et al, 2023 ). Unfortunately, in most cases AR becomes again active, and these patients relapse ( Sowalsky et al, 2015 ).…”