Function And Molecular Mechanism Of Deubiquitinating Enzyme OTUB2 In Lung Cancer

Lung cancer is the second most commonly diagnosed cancer after prostate cancer in men and breast cancer in women worldwide.The occurrence of lung cancer is a complex process involving multi-step,multi-factor and multi-molecular participation.The mechanisms involved in lung cancer remain unclear.Protein is the main performer of life activities,and its expression dysfunction are closely related to the occurrence and development of malignant tumors.Research evidence indicates that ubiquitination of proteins play vital roles in controlling the activity,interactions,subcellular location and stability of many proteins.The enzymes involved in ubiquitination modification include E1 ubiquitin-activating enzymes,E2 ubiquitin-conjugating enzymes,E3 ubiquitin ligases and deubiquitinating enzymes(DUBs).DUBs is responsible for catalyzing that ubiquitin removal from the target protein and reverse the ubiquitination process,DUBs both play an important role in ubiquitination.Due to the complexity of the types and roles of deubiquitinating enzymes,the role of deubiquitinating enzyme in lung cancer and the various mechanisms involved need to be further explored.Although a large number of DUBs have recently been implicated in various tumorigenic progresses,the functions of and DUBs in NSCLC are poorly understood.In order to investigate whether deubiquitinating enzymes have abnormal expression and play important roles in lung cancer,we first use the GEO database to compare the expression of deubiquitinase in lung cancer and matched paracancerous tissues,and search for key deubiquitinating enzymes involved in the development of lung cancer.we demonstrated that OTUB2 overexpressed in NSCLC compared with corresponding nontumorous tissues,and were significantly associated with lymph node metastasis.High expression of OTUB2 is negatively correlated with prognosis and recurrence of lung cancer patients.Furthermore,functional assays showed that OTUB2 promoted the proliferation,invasion and migration ability of NSCLC cells in vitro and vivo.We also found that overexpression of OTUB2 can promote the glycolysis ability of lung cancer cells by regulating AKT/mTOR signaling pathway.Mechanistically,we used immunoprecipitation combined with mass spectrometry to determine that OTUB2 can directly bind to U2AF2 and prevents its ubiquitination.U2AF2 was up-regulated in lung cancer tissues and correlated with OTUB2 expression level.Consistent with the function of OTUB2,cell function test results showed that U2AF2 promoted the invasion and migration ability,proliferation and colony formation ability and glycolysis ability of lung cancer cells in vitro.Finally,the clinical data showed that the high expression of OTUB2,U2AF2 and PGK1 was significantly associated with the prognosis of patients with lung cancer.In summary,we have revealed for the first time the molecular mechanism of the oncogenic roles of OTUB2 in lung cancer cells.These findings provide a new idea for the study of the molecular mechanism of lung cancer,and also provide a new target for the treatment of lung cancer.