Although hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, the molecular pathogenesis of the disease has not been elucidated. Several studies have shown that telomerase activity and hTERT expression are increased in HCCs. In the present study we tried to elucidate hTERT transcriptional and epigenetic regulatory mechanisms in HCC. hTERT expression was tested by real-time PCR and DNA methylation status was assessed by MethyLight and DNA bisulfite sequencing analyses in 106 tissues (64 with HCC and 42 without liver disorders) and also in 7 hepatocarcinoma cell lines (HepG2, HepG3B2, C3A, SNU-182, SNU-398, SBU-449 and SNU-475). hTERT expression levels were inversely correlated with DNA methylation levels in HCC and normal tissues (r=−0.859). hTERT expression was found to be regulated by DNA methylation and histone H3-K9 modifications, affecting the ability of c-myc binding in E-box 1 site in hTERT promoter. Additionally, c-myc siRNA liposomal down-regulation inhibited significantly hTERT expression (p<0.05). Thus, we propose that hTERT is regulated by a combination of epigenetic mechanisms (DNA methylation and histone modifications) and by the transcription factor c-myc in HCC.

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