WDR79 Mediates The Proliferation Of Non-small Cell Lung Cancer Cells By Regulating UHRF1

Lung cancer has the highest incidence and mortality rate in China,causing 1/3 of cancer deaths.About 85%of lung cancers are non-small cell lung cancers(non-small cell lung cancer,NSCLC),and about 70%were at an advanced stage when they were diagnosed,it’s difficult to cure them radically through surgery or radiotherapy or chemotherapy.More worse,despite more than half of the patients in the early stage have accepted some active treatments such as surgery,radiotherapy and chemotherapy,local recurrences or distant metastasises still occur,so the research of the pathogenesis is of great significance for the lung cancer diagnosis and treatment.The WDR79 protein is an important member of the WD-repeat protein family,it is an important component of telomerase and plays an important role in maintaining the stability of telomerase and maintaining the integrity of the genome.It contains the WD repeating domains,which mediate the protein interaction as a platform and play an important role in signal transduction,protein transport,chromosome modification,RNA processing and transcription.Studies have shown that WDR79 protein is highly expressed in non-small cell lung cancer tissues and cell lines,and it can promote the proliferation of non-small cell lung cancer cells by affecting cell cycle and apoptosis.However,the specific molecular mechanism is still unclear.The UHRF1 protein belongs to the UHRF protein family,and it is a nuclear protein closely related to epigenetic modification.It is a necessary semi-methylated DNA binding protein for DNA methylation and has the ubiquitin ligase function.Studies have shown that UHRF1 protein is highly expressed in a variety of human tumor tissues,including bladder cancer,cervical cancer,pancreatic cancer,nasopharyngeal carcinoma and non-small cell lung cancer,etc.;it is involved in tumor cell proliferation and differentiation.Our previous study found that WDR79 protein can promote the proliferation of NSCLC cells,in order to further clarify the molecular mechanism of WDR79 promoting NSCLC proliferation,by Western Blot screening,we found that overexpression of WDR79 in NSCLC cells can upregulate UHRF 1 in protein level,whereas knockdown of WDR79 can downregulate UHRF1.To elucidate the mechanism how WDR79 regulates UHRF1,we used indirect immunofluorescence and immunoprecipitation,and found that WDR79 and UHRF1 co-locate in the NSCLC nucleus and have an interaction.In order to reveal the functional results of their interaction,we used fluorescence quantitative PCR,proteasome blocking and new-protein-synthesis-inhibition experiment,the results showed that WDR79 can inhibit UHRF1 ubiquitination in NSCLC cells,prolong the half-life of UHRF1 and stabilize UHRF1 at the protein level.Considering UHRF1 can promote tumor proliferation,we used MTT experiment and the results demonstrated that WDR79 promotes the proliferation of NSCLC cells by modulating UHRF1.The above studies revealed the molecular mechanism how WDR79 mediates NSCLC cell proliferation by stabilizing UHRF1,and identified WDR79 is a new interactor of the cancer protein UHRF1 is identified.Our findings will not only lay a theoretical foundation for further elucidation of malignant biological behavior of NSCLC,but also provide a new target and a breakthrough point for the diagnosis and treatment of NSCLC.