Phosphorylation-dependent regulation of SPOP by LIMK2 promotes castration-resistant prostate cancer

Background: SPOP, an E3 ubiquitin ligase adaptor, can act either as a tumour suppressor or a tumour promoter. In prostate cancer (PCa), it inhibits tumorigenesis by degrading several oncogenic substrates. SPOP is the most altered gene in PCa (similar to 15%), which renders it ineffective, promoting cancer. The remaining PCa tumours, which retain WT-SPOP, still progress to castration-resistant (CRPC) stage, indicating that other critical mechanisms exist for downregulating SPOP. SPOP is reduced in similar to 94% of WT-SPOP-bearing prostate tumours; however, no molecular mechanism is known for its downregulation. Methods: SPOP was identified as a direct target of LIMK2 using an innovative technique. The reciprocal relationship between SPOP and LIMK2 and its consequences on oncogenicity were analysed using a variety of biochemical assays. To probe this relationship in vivo, xenograft studies were conducted. Results: LIMK2 degrades SPOP by direct phosphorylation at three sites. SPOP promotes LIMK2's ubiquitylation, creating a feedback loop. SPOP's degradation stabilises AR, ARv7 and c-Myc promoting oncogenicity. Phospho-resistant SPOP completely suppresses tumorigenesis in vivo, indicating that LIMK2-mediated SPOP degradation is a key event in PCa progression. Conclusions: While genomically altered SPOP-bearing tumours require gene therapy, uncovering LIMK2-SPOP relationship provides a powerful opportunity to retain WT-SPOP by inhibiting LIMK2, thereby halting disease progression.

Automated summary

This study identified that LIMK2 degrades SPOP by direct phosphorylation and creates a feedback loop to promote oncogenicity in prostate cancer. Understanding the relationship between LIMK2 and SPOP provides a powerful opportunity to inhibit LIMK2 and retain WT-SPOP, effectively halting disease progression.