Mechanistic Study Of Regulation Of Colorectal Cancer Cell Metabolism And Proliferation By Smurf2-ChREBP

Colorectal cancer preferentially utilizes aerobic glycolysis to support cell proliferation.The transcription factor carbohydrate responsive element binding protein(Ch REBP)plays a critical role in promoting glycolysis and cell proliferation in colorectal cancer cells.Post-translational modifications are important for regulating Ch REBP protein level,subcellualr localization and activity.Ubiquitination is reported to be one of the post-translational modifications for Ch REBP.However,the E3 ligase and molecular mechanism for Ch REBP ubiquitination remains unclear.Here we found that the expression of E3 ligase Smad ubiquitination regulatory factor 2(Smurf2)was negatively correlated with that of Ch REBP in cancer by searching the Genevestigator database.We confirmed the negative correlation between levels of Smurf2 and Ch REBP protein in both human colorectal cancer cells and during mouse colorectal cancer progression.After demonstrating that Smurf2 interacted with Ch REBP in colorectal cancer cells using co-immunoprecipitation,we further found that Smurf2 promoted Ch REBP degradation via the ubiquitination proteasome pathway.Ectopic expression of Smurf2 in colorectal cancer cells not only promoted Ch REBP degradation,but also increased oxygen consumption,reduced glucose uptake and decreased cell proliferation.Consistently,Smurf2 knockdown in colorectal cancer cells resulted in Ch REBP accumulation,accompanied by decreased oxygen consumption,increased glucose uptake and cell proliferation.Moreover,we found that the Akt pathway promoted Smurf2 degradation and enhanced Ch REBP protein stability in human colorectal cancer cells.Taken together,our results show that Smurf2,an E3 ligase for Ch REBP,reduces aerobic glycolysis and cell proliferation by decreasing protein stability of Ch REBP via the ubiquitin proteasome pathway in human colorectal cancer cells,which might be regulated by Akt.Our findings may provide new metabolic approaches for the prevention and treatment of colorectal cancer.