Considering the limited efficacy and drug resistance of tyrosine kinase inhibitors, including sunitinib and sorafenib, that are now approved and in clinical used for advanced or metastatic ccRCC treatmnet42, our findings provide a promising therapeutic approach, combinatorial regulation of SHH and WNT affected by SPOP may have the potential to be a more effective ccRCC treatment. Here, SPOP is linked to nonpapillary renal cell carcinoma.