Deregulation of TWIST1 expression by promoter methylation in gastrointestinal cancers

Abstract

TWIST1, a basic helix-loop-helix transcription factor with versatile roles in cancer, is frequently deregulated in cancers, through established pathway perturbations. However. the significance of TWIST1 methylation in the deregulation of TWIST1 in gastrointestinal cancers is not fully clear. This study hypothesized that TWIST1 promoter methylation deregulates TWIST1 expression independent of established deregulators such as the WNT, TGFB, NOTCH and miRNA pathways. To prove this hypothesis, colon, gastric and rectal cancer genomic data comprising gene expression, DNA methylation, and miRNA data were retrieved from the Cancer Genome Atlas cohorts which are publicly available in cancer genomic databases, the Genome Data Commons and the cBioportal.org. About 217 variables comprising expression levels of genes of the WNT, TGFB, NOTCH and miRNA signalling pathways, as well as the beta values of 17 TWIST1 methylation loci were subjected to Principal Component Regression Analysis, and then standard Linear Regression Analysis. The results showed that TWIST1 methylation is a predictor of TWIST1 expression in the gastrointestinal cancers, independent of WNT, TGFB, and NOTCH signalling and miRNA deregulation. The results also showed that different TWIST1 methylation loci may deregulate TWIST1 expression in different cancer types. The inference that can be drawn from this study is that TWIST1 DNA methylation is an important TWIST1 deregulation mechanism in colon, rectal and gastric cancers.