G3BP1 modulates SPOP to promote prostate tumorigenesis.

Speckle-type POZ protein (SPOP), a Cullin 3-based ubiquitin ligase (CUL3SPOP), acts as a prostate-specific tumor suppressor. Loss-of-function mutations in SPOP occur in 10% of primary prostate cancer with a high Gleason grade and poor prognosis. However, it is unclear how the ubiquitin ligase activity of SPOP is controlled and how dysregulation of SPOP contributes to malignant transformation. Here, we identified GTPase Activating Protein (SH3 Domain) Binding Protein 1 (G3BP1) as an interactor and upstream regulator of CUL3SPOP, and it functions as an inhibitor of CUL3SPOP ubiquitin ligase, suggesting a distinctive mode of CUL3SPOP inactivation that aggravates prostate cancer.