Project description:To examine origin firing upon CDT1 overexpression, EdUseq-HU was performed in HCT116 cells with normal expression levels of CDT1 (OFF) and HCT116 cells with CDT1 overexpression (ON)
Project description:Colorectal adenomas are precursor lesions of colorectal cancers and represent clonal amplifications of single cells from colonic crypts. DNA methylation patterns specify cell-type identity during cellular differentiation and therefore provide novel opportunities for the molecular analysis of tumors. We have now analyzed DNA methylation patterns in colorectal adenomas and identified three biologically defined subclasses that describe different intestinal crypt differentiation stages. Importantly, colorectal carcinomas could be classified into the same methylation subtypes, reflecting their shared cell-types of origin with adenomas. Further data analysis also revealed significantly reduced overall survival for one of the subtypes. Our results establish a novel concept for understanding the methylation patterns observed in colorectal cancer and provide opportunities for tumor subclassification and patient stratification.
Project description: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.