Epigenetic Reprogramming Modulates Malignant Properties of Human Liver Cancer Cells

Reversal of DNA hypermethylation and associated gene silencing is an emerging cancer therapy approach. In this context we have addressed the impact of epigenetic alterations and local microenvironment on the functional and transcriptional reprogramming of hepatic cancer stem cells. (CSCs) using the DNMT1 inhibitor Zebularine (ZEB). We show for the first time that cellular context is a critical determinant in the response to DNMT1 inhibition resulting in either a long term epigenetically driven malignant reprogramming or an effective antitumor therapeutic reprogramming. Furthermore, permanent reduction of DNMT1 protein level renders the HCC cell lines insensitive to both DNMT1 inhibition and cellular context. These results emphasize the importance of decoding the mechanisms involved in therapeutic application of DNA demethylating agents. Huh7 and PLC treated with ZEB, and Huh7 depleted for DNMT1