Fig. 10. Schematic representation of the proposed model for the aversive relationship between mutant SPOP and ERG in prostate cancer.

On the left side, SPOP mutant prostate cancer tumorigenesis is depicted. SPOP mutant tumors impair the degradation of substrate proteins such as AR activators (e.g, TRIM24) and ZMIND11, which ultimately triggers the AR pathway and dampens the ERG signaling. In this context, SPOP mutant tumors are more susceptible to ADT therapy. On the right side, TMPRSS2-ERG mutant tumorigenesis is depicted. ERG binds to the promoter of wild-type SPOP, upregulating its protein expression. Consequently, AR activators and ZMYND11 substrate proteins get degraded, leading to the AR pathway downregulation and unleashing the ERG signaling pathway. TMPRSS2-ERG mutant tumors are thus sensitive to high-dose androgen therapy or SPOP inhibition.