MicroRNA-29a induces loss of 5-hydroxymethylcytosine and promotes metastasis of hepatocellular carcinoma through a TET–SOCS1–MMP9 signaling axis

Ten eleven translocation (TET) enzymes convert 5-methylcytosine (5-mC) to 5-hydroxy-methylcytosine (5-hmC) and have crucial roles in biological and pathological processes by mediating DNA demethylation, however, the functional role of this epigenetic mark and the related enzymes in hepatocellular carcinoma (HCC) progression remains unknown. Here, we demonstrated that TET-family enzymes downregulation was one likely mechanism underlying 5-hmC loss in HCC. We found that miR-29a overexpression increased DNA methylation of suppressor of cytokine signaling 1 (SOCS1) promoter was associated with HCC metastasis in vitro and in vivo. Furthermore, miR-29a silenced anti-metastatic SOCS1 through direct TET-family targeting, resulting in SOCS1 promoter demethylation inhibition. Chromatin immunoprecipitation analyses confirmed that TET1 regulated SOCS1 expression through binding to the promoter region of SOCS1. Finally, miR-29a overexpression correlated with poor clinical outcomes and TET–SOCS1–matrix metalloproteinase (MMP) 9 axis silencing in HCC patients. In conclusion, our findings demonstrate that 5-hmC loss is an epigenetic hallmark of HCC, and miR-29a is an important epigenetic modifier, promoting HCC metastasis through TET–SOCS1–MMP9 axis silencing. The results offer a new strategy for epigenetic cancer therapy.