DNA Methylation of TGFβ Target Genes: Epigenetic Control of TGFβ Functional Duality in Liver Cancer

Transforming growth factor beta (TGF beta) plays a key role in liver carcinogenesis. However, its action is complex, since TGF beta exhibits tumor-suppressive or oncogenic properties, depending on the tumor stage. At an early stage TGF beta exhibits cytostatic features, but at a later stage it promotes cell growth and metastasis, as a potent inducer of epithelial to mesenchymal transition (EMT). Here, we evaluated DNA methylation as a possible molecular mechanism switching TGF beta activity toward tumor progression in hepatocellular carcinoma (HCC). We report that decitabine, a demethylating agent already used in the clinic for the treatment of several cancers, greatly impairs the transcriptional response of SNU449 HCC cells to TGF beta. Importantly, decitabine was shown to induce the expression of EMT-related transcription factors (e.g., SNAI1/2, ZEB1/2). We also report that the promoter of SNAI1 was hypomethylated in poor-prognosis human HCC, i.e., associated with high grade, high AFP level, metastasis and recurrence. Altogether, the data highlight an epigenetic control of several effectors of the TGF beta pathway in human HCC possibly involved in switching its action toward EMT and tumor progression. Thus, we conclude that epidrugs should be carefully evaluated for the treatment of HCC, as they may activate tumor promoting pathways.

Automated summary

The study found that DNA methylation may affect the activity of TGF beta in liver cancer, promoting EMT and tumor progression. By using decitabine, the transcriptional response of HCC cells to TGF beta was impaired, inducing the expression of EMT-related transcription factors, and hypomethylation of the SNAI1 promoter associated with poor prognosis in human HCC was identified.