GSK3B

This study investigated DNA methylation profiles in 259 sporadic colorectal cancers, aiming to identify microsatellite instability (MSI)-associated signatures beyond the CIMP phenotype and MLH1 promoter hypermethylation. Researchers discovered 656 differentially methylated CpG sites linked to MSI, including hypermethylation of LRP6, GSK3B, and CDK12, genes involved in WNT signaling and transcriptional regulation. The study also revealed heterogeneity within MSI CRCs, with co-occurrence of MLH1 and TXNRD1 promoter hypermethylation. Furthermore, anatomical location was found to be a major determinant of the CRC methylome, contributing to improved molecular stratification of the disease.

This study demonstrates that MEK1/2 inhibitors, targeting the Ras-MAPK pathway, induce AXIN1 protein loss in colorectal cancer cell lines and patient-derived organoids. Unlike GSK3 inhibitors, this loss is not attributed to altered AXIN1 protein stability or post-translational modifications, nor to a significant reduction in its transcript levels. Analyses revealed that MEK1/2 inhibitors reduce global protein synthesis via an mTOR-associated pathway, an effect sufficient to cause AXIN1 loss. Co-treatment with tankyrase inhibitors was shown to partially prevent this AXIN1 reduction.