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

Kevin Bévant,Abdel Hady A Abdel Wahab,Matthis Desoteux,Cédric Coulouarn,Sabrin A Abdel Wahab,Ayman Mohamed Metwally

doi:10.3390/cells10092207

Abstract

Transforming growth factor beta (TGFβ) plays a key role in liver carcinogenesis. However, its action is complex, since TGFβ exhibits tumor-suppressive or oncogenic properties, depending on the tumor stage. At an early stage TGFβ 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 TGFβ 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 TGFβ. 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 TGFβ 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.

Highlights

Liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer related death [1]
These results suggested that the epigenetic inhibition of SMAD4 expression by DNA methylation in poor-prognosis Hepatocellular carcinoma (HCC) may contribute to the loss of the tumor-suppressive arm of the canonical TGFβ pathway, as is documented in regard to other tumors, including pancreatic and colorectal carcinoma [31,32]
Decitabine may not be the treatment of choice for early-stage HCC, as it may switch the actions of TGFβ toward pro-metastatic features

Summary

Introduction

Liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer related death [1]. Of liver primary tumors, with approximately 626,000 cases diagnosed and 598,000 deaths each year, worldwide [1]. HCC incidence has increased dramatically over the last 20 years, including in high-incidence countries [1]. In France, the incidence of HCC has increased in the last 20 years. Nonalcoholic fatty liver diseases represent the fastest growing cause of HCC, in France, and in the USA and the UK [2]. In Egypt, HCC is the second most frequent cause of cancer incidence and mortality in men [1]. Recent investigations have shown the increasing importance of HCV infection in the etiology of HCC, estimated to account for >50% of HCC cases. Egypt exhibits the highest prevalence of HCV worldwide, and has experienced a dramatic rise in HCC rates [4]. Significant progress has been made in the management of patients, HCC treatment represents an important clinical challenge [5]

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