Carbohydrate responsive element binding protein promotes colorectal carcinogenesis by regulating the Wnt/beta-catenin pathway

ChREBP is a glucose-responsive transcription factor involved in glycolysis and de novo lipogenesis. Elevated ChREBP levels were observed in human colorectal cancer (CRC) samples and correlated with poor 5-year survival rates in patients. To investigate the role and mechanism of ChREBP in colorectal carcinogenesis in vivo, we used ChREBP knockout mice, which were intraperitoneally injected with azoxymethane (AOM) followed by dextran sulfate sodium (DSS) in drinking water. In the AOM/DSS-induced colorectal cancer model, carcinogenesis was reduced in ChREBP null mice. In the initial phases of colorectal carcinogenesis, ChREBP deficiency was associated with diminished epithelial cell proliferation and a lower number of aberrant crypt foci (ACF), but it had no impact on DNA damage or the severity of colitis. The key transcription factor beta-catenin and Wnt target gene expression were both decreased in the colons of ChREBP null mice and in ChREBP-knockdown Caco-2 colorectal cancer cells. In vitro studies showed that ChREBP knockdown promoted beta-catenin phosphorylation and reduced beta-catenin levels and nuclear localization in Caco-2 cells. Conversely, ChREBP overexpression was sufficient to promote beta-catenin accumulation, nuclear localization, and transcriptional activity in human HEK293T cells, thereby contributing to compensatory proliferation and tumorigenesis. Given its elevated expression in human colorectal cancer, ChREBP may represent a potential therapeutic target. The correlation between ChREBP-mediated Wnt signaling activation and colorectal carcinogenesis would provide deeper insights into the link between metabolic dysfunction and colorectal cancer.