Open Access Research article

Dynamic imbalance between cancer cell subpopulations induced by Transforming Growth Factor Beta (TGF-β) is associated with a DNA methylome switch

Marion Martin1, Pierre-Benoit Ancey1, Marie-Pierre Cros1, Geoffroy Durand2, Florence Le Calvez-Kelm2, Hector Hernandez-Vargas1* and Zdenko Herceg1*

Author Affiliations

1 Epigenetics Group. International Agency for Research on Cancer (IARC), 150 rue Albert-Thomas, 69008 Lyon, France

2 Genetic Cancer Susceptibility Group. International Agency for Research on Cancer (IARC), 150 rue Albert-Thomas, 69008 Lyon, France

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BMC Genomics 2014, 15:435  doi:10.1186/1471-2164-15-435

Published: 5 June 2014



Distinct subpopulations of neoplastic cells within tumors, including hepatocellular carcinoma (HCC), display pronounced ability to initiate new tumors and induce metastasis. Recent evidence suggests that signals from transforming growth factor beta (TGF-β) may increase the survival of these so called tumor initiating cells leading to poor HCC prognosis. However, how TGF-β establishes and modifies the key features of these cell subpopulations is not fully understood.


In the present report we describe the differential DNA methylome of CD133-negative and CD133-expressing liver cancer cells. Next, we show that TGF-β is able to increase the proportion of CD133+ cells in liver cancer cell lines in a way that is stable and persistent across cell division. This process is associated with stable genome-wide changes in DNA methylation that persist through cell division. Differential methylation in response to TGF-β is under-represented at promoter CpG islands and enriched at gene bodies, including a locus in the body of the de novo DNA methyl-transferase DNMT3B gene. Moreover, phenotypic changes induced by TGF-β, including the induction of CD133, are impaired by siRNA silencing of de novo DNA methyl-transferases.


Our study reveals a self-perpetuating crosstalk between TGF-β signaling and the DNA methylation machinery, which can be relevant in the establishment of cellular phenotypes. This is the first indication of the ability of TGF-β to induce genome-wide changes in DNA methylation, resulting in a stable change in the proportion of liver cancer cell subpopulations.

HCC; Tumor-initiating cells; CD133; DNA methylation; TGF-β pathway