XBP1s Regulates Tumor Cells Proliferation Through Inhibiting Tumor Suppressor TAp73

Colon carcinoma is the third most common cancer,and the most common visceral cancer.The morbidity and the mortality of colon carcinoma is very high,and is the third leading cause of cancer death.The increase of new cases per year reached 1.4 million,and recent years,the age of patients suffering from colon carcinoma is trending younger.Despite of this high morbidity,the molecular mechanism that regulates the tumorigenesis of colon carcinoma has not been totally elucidated.X-box binding protein 1(XBP1)has been characterized as a bZIP(basic-region leucine zipper)transcription factor.XBP1 yields two isoforms: the unspliced XBP1(XBP1-u),and the spliced XBP1(XBP1-s).Upon exposure to endoplasmic reticulum stress(ER stress),Inositor-requireing enzyme 1?(IRE1?)splices 26 nucleotides from the coding region of XBP1-u mRNA and produces XBP1-s,which plays critical roles in endoplasmic reticulum and unfolded protein response.XBP1-s is highly expressed in various kinds of tumors,including lymphoma,acute myeloid leukemia,bone marrow cancer,and breast cancer.XBP1-s could positively regulate cell proliferation,and subsequently,promote tumorigenesis.Despite of its critical role,the molecular mechanism underlying the role of XBP1-s in tumorigenesis has not been fully elucidated.p73 is a member of p53 family,and has a high homology in both nucleotides sequence and protein structure with other members of the family,i.e.,p53 and p63.There are two isoforms of p73:(35)Np73and TAp73.Among them,TAp73 is similar to p53 as it exerts tumor suppressor activity,while(35)Np73,in contrast,is oncogenic.However,different from p53 which is oftenly mutated in tumors,p73 is rarely mutated in tumor.Despite that it plays important role in inhibiting tumorigenesis,the mechanism of its expression regulation remains unclear.Herein,we investigated the role of XBP1-s in regulating the expression level of p53,and the molecular mechanism underlying it,as well as whether XBP1-s promotes tumor cells proliferation,and subsequently,tumorigenesis,via regulating TAp73 expression.In this study,we first examined the effect of ER stress and overexpressing XBP1-s on the expression level of TAp73.We found that both ER stress and XBP1-s overexpression significantly suppressed TAp73 mRNA and protein expression levels,indicating that XBP1-s could negatively regulate TAp73.We also examined the role of XBP1-s/TAp73 in regulating colon carcinoma cells proliferation and colony formation potential,and found that while XBP1-s accumulation promotes cells proliferation and colony formation potentials,TAp73 overexpression could canceled these effects.These results clearly indicate that XBP1-s enhances tumor cells proliferation and colony formation potentials through negative regulation on TAp73.Furthermore,we found that XBP1-s regulation on TAp73 expression occurs in a p53-independent manner.We showed,through chromatin immunoprecipitation and reporter assay,that XBP1-s could bind to the-513 to-222 region of TAp73 promoter,and regulates TAp73 transcriptional activity.In summary,we found that XBP1-s is a novel regulator of TAp73 that could regulate TAp73 transcriptional activity,and subsequently promote colon carcinoma cells proliferation and colony formation potentials.Our findings not only unravel a novel mechanism of XBP1-s in promoting tumorigenesis,but also the regulatory mechanism of TAp73.