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.
Sherly I Celada,
"Combined Inhibition of SKP2 and Androgen Receptor Suppressed Prostate Tumorigenesis by Activating Autophagy and Apoptosis"
ETD Collection for Tennessee State University.