ERK1/2 inhibits Cullin 3/SPOP-mediated PrLZ ubiquitination and degradation to modulate prostate cancer progression

The gene encoding the E3 ubiquitin ligase substrate-binding adaptor SPOP is frequently mutated in prostate cancer (PCa), but how SPOP functions as a tumor suppressor and contributes to PCa pathogenesis remains poorly understood. Prostate Leucine Zipper (PrLZ) serves as a prostate-specific and androgen-responsive gene, which plays a pivotal role in the malignant progression of PCa. However, the upstream regulatory mechanism of PrLZ protein stability and its physiological contribution to PCa carcinogenesis remain largely elusive. Here we report that PrLZ can be degraded by SPOP. PrLZ abundance is elevated in SPOP-mutant expressing PCa cell lines and patient specimens. Meanwhile, ERK1/2 might regulate SPOP-mediated PrLZ degradation through phosphorylating PrLZ at Ser40, which blocks the interaction between SPOP and PrLZ. In addition, we identify IL-6 might act as an upstream PrLZ degradation regulator via promoting its phosphorylation by ERK1/2, leading to its impaired recognition by SPOP. Thus, our study reveals a novel SPOP substrate PrLZ which might be controlled by ERK1/2-mediated phosphorylation, thereby facilitating to explore novel drug targets and improve therapeutic strategy for PCa.

Automated summary

The gene encoding SPOP is frequently mutated in prostate cancer (PCa). This study reveals that SPOP functions as a tumor suppressor by degrading PrLZ, a prostate-specific and androgen-responsive gene. ERK1/2 regulates SPOP-mediated PrLZ degradation through phosphorylation, while IL-6 acts as an upstream regulator of PrLZ degradation by promoting its phosphorylation.