ZMIZ2-USP7-β-catenin Axis Affects Growth Of Colorectal Cancer

Colorectal cancer(CRC)is a common clinical malignancy,whose morbidity and mortality are both very high.It is a grave threat for human health and many families to live normal life.So far,there is still no completely appropriate treatment to cure colorectal cancer patients.Therefore,it is very important and urgent to study the relevant mechanism about the occurrence and development of colorectal cancer,so we can develop appropriate treatment methods through clinical application and apply them in therapy.Although long non-coding RNA(LncRNA)has no protein-coding ability,it can participate in a variety of physiological reactions through different mechanisms and thus affect the process of life.In tumors,a variety of LncRNAs are abnormal,and their functions are diverse.However,LncRNA accounts for a large proportion in the human genome,and it still needs to be further studied about its explicit mechanism in tumorigenesis and development.In this study first we identified a LncRNA named LINC00265,which is abnormally overexpressed in human colorectal cancer,and it was strongly positively correlated with the mRNA level of ZMIZ2,then we conducted gene ontology(GO)analysis on the significantly changed genes associated with LINC00265,we found that LINC00265 enhance the signaling of Wnt/β-catenin and β-catenin target genes.And LINC00265 enhances β-catenin signaling through ZMIZ2 protein.In order to understand the exactly how LINC00265 enhances the signaling of β-catenin,our experiments have shown that the interaction between ZMIZ2 and β-catenin is affected by the level of LINC00265.After that,we found that ZMIZ2 stabilized β-catenin through K6-,K33-and K48-linked deubiquitination through the protein stability related experiments,so as to enhance the signaling of β-catenin.Then we study the specific deubiquitination mechanism of ZMIZ2 on β-catenin protein,to evaluate which deubiquitinases(DUBs)mediated β-catenin stability with luciferase reporter screen,we found that ZMIZ2 can stabilize β-catenin through a deubiquitinase USP7.Moreover,ZMIZ2 can enhance the signaling of β-catenin by recruiting the deubiquitinase USP7 to deubiquitate and stabilize β-catenin.In addition,LINC00265 and ZMIZ2 can promoted the malignant proliferation of colorectal cancer cells mainly by enhancing the β-catenin signaling.In summary,LINC00265 can enhance β-catenin signaling via ZMIZ2.ZMIZ2 enhances signaling strength by recruiting USP7 to deubiquitinate and stabilize β-catenin.In addition,LINC00265 and ZMIZ2 can promote the malignant proliferation of colorectal cancer cells depend on β-catenin protein.In summary,LINC00265 can enhance β-catenin signaling by recruiting USP7 to deubiquitinate snd stabilize β-catenin via ZMIZ2,thereby the enhanced β-catenin may promote the malignant proliferation of colorectal cancer cells.Our study is helpful to understand the mechanism of LncRNA in the development and progression of colorectal cancer,and it is likely to provide new therapeutic targets for the treatment of colorectal cancer.