Ufmylation Is Activated in Renal Cancer and Is Not Associated with von Hippel-Lindau Mutation.

Clear cell renal cell carcinoma is the most common in all of the renal cancers; however, it lacks ideal molecular target for treatment. In the present study, we identified that ufmylation, a novel ubiquitin-like modification, was significantly upregulated in renal cancer tissues. Ufmylation is known to be closely associated with endoplasmic reticulum (ER) stress and protein quality control. To explore the relation between ufmylation and protein degradation pathways in renal cancer cells, we pharmacologically altered the ubiquitin-proteasome (UPS) and autophagy pathways. We found that the ufmylation levels were not varied by autophagy activation or inhibition. Consistently, the LC3 conversion, as an important biomarker of autophagy, was comparable between renal caner tissues and para-cancer tissues, indicating that the increase of ufmylation in renal cancer may be not related with autophagy. In contrast, blocking UPS with MG132 activated ufmylation in renal cancer cells, suggesting that the activation of ufmylation in renal cancer may be associated with the UPS activity. However, the ufmylation levels were not associated with mutations of the von Hippel-Lindau (VHL) gene, a specific E3 ligase of the UPS and has high mutation rate in renal cancer. Besides, we found that sunitinib, a multi-targeted tyrosine kinase inhibitor, could significantly inhibit ufmylation, whereas overexpression of active Ufm1 partially inhibited the antitumor effects of sunitinib. These results highlight that ufmylation might be a novel molecular candidate for renal cancer.