Notably, our findings show that HnRNPK knockdown can impair the cell growth and cell cycle progression of PrCa cell lines, and prostate cancer-associated SPOP mutants, including F102C and W131G, which are clustered in its substrate-recruiting MATH domain, restrain its capability to bind and promote HnRNPK polyubiquitination and degradation. The gene discussed is SPOP; the disease is prostate cancer.