Clear cell renal cell carcinoma (ccRCC) is the most common subtype of
renal cell carcinoma and has the highest mortality rate. For metastatic RCC, systemic
drug therapy is the most important method in addition to surgical
tumor reduction. In recent years,
tyrosine kinase inhibitors (TKIs) targeting the angiogenesis have been applied to treat ccRCC and achieved profound
therapeutic effects. It has been reported that most patients receiving antiangiogenic
therapy will develop resistance within 15 months. The mechanism of resistance to targeted
therapy is extremely complex and has not been clarified. Ovarian
tumor-associated
protease domain-containing
proteins (OTUDs) belonging to DUBs play a critical role in the
tumorigenesis of solid
tumors. However, the specific role of OTUDs in ccRCC is still elusive. Here, we investigated the clinicopathological role of OTUD family members in ccRCC. We demonstrated that OTUD1 was downregulated in
renal cancer and involved in the poor prognosis of
renal cancer. Then, we showed that OTUD1 inhibits
cancer cell growth. Moreover, analysis of OTUD1
RNA-seq data indicated that OTUD1 inhibition triggers the AKT and
NF-kappa B pathways in
renal cancer cells. Furthermore, OTUD1 interacts with PTEN and regulates its stability. Subsequently, we revealed that downregulation of OTUD1 contributes to the sensitivity of
renal cancer cells to TKIs, and this effect was blocked by TNF/
NF-kappa B inhibitors and AKT inhibitors. Thus, we identified that the OTUD1-PTEN axis suppresses
tumor growth and regulates the resistance of
renal cancer to TKIs.