KDM5B Is Essential for the Hyperactivation of PI3K/AKT Signaling in Prostate Tumorigenesis

KDM5B (lysine[K]-specific demethylase 5B) is frequently upregulated in various human cancers including prostate cancer. KDM5B controls H3K4me3/2 levels and regulates gene transcription and cell differentiation, yet the contributions of KDM5B to prostate cancer tumorigenesis remain unknown. In this study, we investigated the functional role of KDM5B in epigenetic dysregulation and prostate cancer progression in cultured cells and in mouse models of prostate epithelium–specific mutant Pten/Kdm5b. Kdm5b deficiency resulted in a significant delay in the onset of prostate cancer in Pten-null mice, whereas Kdm5b loss alone caused no morphologic abnormalities in mouse prostates. At 6 months of age, the prostate weight of Pten/Kdm5b mice was reduced by up to 70% compared with that of Pten mice. Pathologic analysis revealed Pten/Kdm5b mice displayed mild morphologic changes with hyperplasia in prostates, whereas age-matched Pten littermates developed high-grade prostatic intraepithelial neoplasia and prostate cancer. Mechanistically, KDM5B governed PI3K/AKT signaling in prostate cancer in vitro and in vivo. KDM5B directly bound the PIK3CA promoter, and KDM5B knockout resulted in a significant reduction of P110α and PIP3 levels and subsequent decrease in proliferation of human prostate cancer cells. Conversely, KDM5B overexpression resulted in increased PI3K/AKT signaling. Loss of Kdm5b abrogated the hyperactivation of AKT signaling by decreasing P110α/P85 levels in Pten/Kdm5b mice. Taken together, our findings reveal that KDM5B acts as a key regulator of PI3K/AKT signaling; they also support the concept that targeting KDM5B is a novel and effective therapeutic strategy against prostate cancer

Combined Inhibition of SKP2 and Androgen Receptor Suppressed Prostate Tumorigenesis by Activating Autophagy and Apoptosis

Increased levels of SKP2 (S-phase kinase-associated protein 2), an E3 ubiquitin ligase, is frequently seen in advanced stages of prostate cancer (PCa). Association between SKP2 and the ubiquitin-mediated degradation of androgen receptor (AR) has been observed in PCa. Despite these associations, the molecular mechanisms responsible for the proto-oncogenic effects of SKP2 in PCa remain elusive. The transcription factor FOXA1 (Forkhead box protein A1) is known to induce AR activity, and by doing so cause the activation of AR target genes. Deregulation of the AR and FOXA1 has been found to contribute to the progression of PCa and castration-resistant prostate cancer (CRPC). We hypothesized that SKP2 impacts the function of both AR and FOXA1 contributing to the progression of CRPC. Here we report that SKP2 inactivation increased AR and FOXA1 levels in C4-2B and 22Rv1 cells, two CRPC cell lines. Mechanistically, in vivo ubiquitination assay using HA-Ub constructs demonstrated that SKP2 is an E3 ubiquitin ligase for FOXA1 catalyzing the synthesis of K6 and K29-linked polyubiquitin chains. Furthermore, SKP2 knockdown significantly inhibited cellular proliferation and restored sensitivity to the AR antagonist (MDV3100) in C4-2B and 22Rv1 cells. While combined exposure to the AR antagonist (MDV3100) and a SKP2 inhibitor significantly reduced cellular proliferation in vitro and reduced tumorigenesis in Pten/Trp53 mutant mice in vivo, a result of autophagy and apoptosis induction. Our findings present a potential SKP2 therapeutic target in order to inhibit CRPC malignancy

Lysosome‐dependent FOXA1 ubiquitination contributes to luminal lineage of advanced prostate cancer

Changes in FOXA1 (forkhead box protein A1) protein levels are well associated with prostate cancer (PCa) progression. Unfortunately, direct targeting of FOXA1 in progressive PCa remains challenging due to variations in FOXA1 protein levels, increased FOXA1 mutations at different stages of PCa, and elusive post‐translational FOXA1 regulating mechanisms. Here, we show that SKP2 (S‐phase kinase‐associated protein 2) catalyzes K6‐ and K29‐linked polyubiquitination of FOXA1 for lysosomal‐dependent degradation. Our data indicate increased SKP2:FOXA1 protein ratios in stage IV human PCa compared to stages I–III, together with a strong inverse correlation (r = −0.9659) between SKP2 and FOXA1 levels, suggesting that SKP2–FOXA1 protein interactions play a significant role in PCa progression. Prostate tumors of Pten/Trp53 mice displayed increased Skp2–Foxa1–Pcna signaling and colocalization, whereas disruption of the Skp2–Foxa1 interplay in Pten/Trp53/Skp2 triple‐null mice demonstrated decreased Pcna levels and increased expression of Foxa1 and luminal positive cells. Treatment of xenograft mice with the SKP2 inhibitor SZL P1‐41 decreased tumor proliferation, SKP2:FOXA1 ratios, and colocalization. Thus, our results highlight the significance of the SKP2–FOXA1 interplay on the luminal lineage in PCa and the potential of therapeutically targeting FOXA1 through SKP2 to improve PCa control