Molecular Interplay between AURKA and SPOP Dictates CRPC Pathogenesis via Androgen Receptor.

Simple Summary Prostate cancer is the most common type of cancer in men. Early stage prostate cancer is treatable. However, remission eventually occurs in vast majority of patients, giving rise to castration-resistant prostate cancer (CRPC), which is incurable with current therapies. Aurora A (AURKA) is overexpressed in all stages of prostate cancer including CRPC. AURKA inhibition has shown efficacy in reducing cancer burden in clinical trials, however, no AURKA inhibitor has been approved by the FDA, primarily because AURKA inhibition is toxic to normal cells. Thus, identification of downstream targets of AURKA provides an alternative approach to regulate AURKA-mediated malignancy. We identified a tumor suppressor protein named SPOP as AURKA target. SPOP is rendered ineffective in prostate cancer by genomic mutations promoting cancer. We show that AURKA degrades SPOP, which promotes malignancy and drug-resistance. Thus, AURKA inhibition provides a powerful tool to retain SPOP, thereby treating the disease and inhibiting its progression. SPOP, an adaptor protein for E3 ubiquitin ligase can function as a tumor-suppressor or a tumor-enhancer. In castration-resistant prostate cancer (CRPC), it inhibits tumorigenesis by degrading many oncogenic targets, including androgen receptor (AR). Expectedly, SPOP is the most commonly mutated gene in CRPC (15%), which closely correlates with poor prognosis. Importantly, 85% of tumors that retain wild-type SPOP show reduced protein levels, indicating that SPOP downregulation is an essential step in CRPC progression. However, the underlying molecular mechanism remains unknown. This study uncovered the first mechanism of SPOP regulation in any type of cancer. We identified SPOP as a direct substrate of Aurora A (AURKA) using an innovative technique. AURKA directly phosphorylates SPOP at three sites, causing its ubiquitylation. SPOP degradation drives highly aggressive oncogenic phenotypes in cells and in vivo including stabilizing AR, ARv7 and c-Myc. Further, SPOP degrades AURKA via a feedback loop. SPOP upregulation is one of the mechanisms by which enzalutamide exerts its efficacy. Consequently, phospho-resistant SPOP fully abrogates tumorigenesis and EMT in vivo, and renders CRPC cells sensitive to enzalutamide. While genomic mutations of SPOP can be treated with gene therapy, identification of AURKA as an upstream regulator of SPOP provides a powerful opportunity for retaining WT-SPOP in a vast majority of CRPC patients using AURKA inhibitors +/- enzalutamide, thereby treating the disease and inhibiting its progression.