Molecular insights for the tumor suppressor role of SPOP in prostate cancer.

Speckle-type POZ protein (SPOP) functions as a substrate adaptor within the cullin 3-based E3 ubiquitin ligase complex, playing an essential role in regulating diverse cellular processes by targeting specific proteins toward ubiquitination and proteasomal degradation. Aberrations in SPOP-driven proteolytic pathways have been implicated in the initiation and progression of prostate cancer. In this context, SPOP appears to function largely as a tumor suppressor by mediating the degradation of several oncogenic proteins such as AR, SRC3, CDC20, MYC, ERG, PD-L1, and BRD4. Mutations that impair SPOP function can result in the promotion of these substrates' oncogenic function, contributing to tumor initiation and progression. Hence, a deeper investigation into the molecular mechanisms of SPOP in prostate cancer will provide novel insights into its physiological function in oncogenesis and drug development. In this review, we summarize SPOP's tumor suppressor functions and structural features, upstream regulatory mechanisms, and SPOP-targeting therapeutic strategies in prostate cancer.