| Renal cell carcinoma is among the 10 most common cancers,representing 3.7% of all new cancer cases.The incidence has been kept rising worldwide and the prognosis remains poor.Clear cell renal cell carcinoma(cc RCC)what a renal cortical tumor characterized by malignant epithelial cells,is the most common type of renal carcinomas,constituting 80% of all cases.Renal cell carcinoma treatment has evolved dramatically over the past decade from two to thirteen representing seven distinct effective treatment mechanisms encompassing targeted and immunotherapeutic agents by FDA.However,drug treatment will eventually lead to drug resistance,so that it is important to find its potential molecular mechanism.Ubiquitination is a post-translational protein modification involved in regulating a variety of cellular processes,including cell cycle and apoptosis that play key roles in cancer development.Homologous to the E6-associated protein carboxyl terminus domain containing3(HECTD3)is an E3 ubiquitin ligase.It is reported that HECTD3 can increase cell resistance to chemotherapy in breast cancer,ovarian cancer and esophageal squamous cell carcinoma,but with unknown functions in renal cell carcinoma.Here,we show that Cyclin D1 as an HECTD3-interacting protein.HECTD3 depletion leads to a decreased cell growth and synthesis of DNA,Overexpression of HECTD3 likewise increases cell growth and synthesis of DNA in these cancer cells.However,whereas overexpression of Cyclin D1 partially rescues HECTD3 depletion–induced inhibition of cell growth and DNA synthesis.HECTD3 was positively expressed in renal cell tissues and was generally highly expressed in renal cell carcinoma cell lines.While HETCD3 did not affect the sensitivity of renal clear cell carcinoma cells to chemotherapy drugs.HECTD3 promotes Cyclin D1 ubiquitination with nondegradative polyubiquitin chains by direct interacting with the Cyclin D1 through its N-terminal destruction of C domain.HECTD3 does not target Cyclin D1 for degradation but stabilize it.These findings suggest that HECTD3 promotes cell survival through stabilizing Cyclin D1.Although clinical progress has been made in the treatment of patients with renal cell carcinoma,the efficacy is not satisfactory.In this study,for the first time,Cyclin D1 is the new substrate of HECTD3 and the potential molecular mechanism of HECTD3 in promoting tumor function has been elucidated,which not only increases our understanding of the oncogene function of HECTD3 and Cyclin D1,but also provides theoretical basis for HECTD3 as a tumor treatment target.These results suggest that HECTD3 is a prosurvival E3 ligase and provides novel potential therapeutic targets for cancer. |
