Epigenetic Alteration by DNA Promoter Hypermethylation of Genes Related to Transforming Growth Factor-β (TGF-β) Signaling in Cancer

Abstract

Epigenetic alterations in cancer, especially DNA methylation and histone modification, exert a significant effect on the deregulated expression of cancer-related genes and lay an epigenetic pathway to carcinogenesis and tumor progression. Global hypomethylation and local hypermethylation of CpG islands in the promoter region, which result in silencing tumor suppressor genes, constitute general and major epigenetic modification, the hallmark of the neoplastic epigenome. Additionally, methylation-induced gene silencing commonly affects a number of genes and increases with cancer progression. Indeed, cancers with a high degree of methylation (CpG island methylator phenotype/CIMP) do exist and represent a distinct subset of certain cancers including colorectal, bladder and kidney. On the other hand, signals from the microenvironment, especially those from transforming growth factor-β (TGF-β), induce targeted de novo epigenetic alterations of cancer-related genes. While TGF-β signaling has been implicated in two opposite roles in cancer, namely tumor suppression and tumor promotion, its deregulation is also partly induced by epigenetic alteration itself. Although the epigenetic pathway to carcinogenesis and cancer progression has such reciprocal complexity, the important issue is to identify genes or signaling pathways that are commonly silenced in various cancers in order to find early diagnostic and therapeutic targets. In this review, we focus on the epigenetic alteration by DNA methylation and its role in molecular modulations of the TGF-β signaling pathway that cause or underlie altered cancer-related gene expression in both phases of early carcinogenesis and late cancer progression.

Supratentorial and spinal pediatric ependymomas display a hypermethylated phenotype which includes the loss of tumor suppressor genes involved in the control of cell growth and death

“…Hypomethylation therapies have been approved for use in liquid tumors [29]. However, these therapies risk activating methylated oncogenes.…”

The roles of TGFβ in the tumour microenvironment

“…TGFβ and the TGFβ signalling pathway have been linked with histone and promoter modifications 136 . The hypermethylation of promoter regions of a gene mainly results in the silencing of that gene.…”

Clinical significance of promoter hypermethylation of genes in ovarian cancer

“…The TGF-beta superfamily now contains around 40 secreted ligands [65], which play diverse and multifunctional roles in cell proliferation, differentiation, migration, immune response, angiogenesis and apoptosis [66]. It has been published that the hypermethylation of genes in TGF-beta signaling pathway were associated with many malignancies such as gastric [67], hepatocellular carcinoma [68] TGFBI hypermethylation was detected in two OC cell lines (ES-2 and OVCAR-3) and was present in 60.5% of OC patients, 27.8% of borderline ovarian diseases, and none of the normal cases.…”