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

Abstract

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.

IL‐17A promotes cell migration and invasion of glioblastoma cells via activation of PI3K/AKT signalling pathway

“…MMP‐2/9 plays an important role in cancer metastasis, and IL‐17A is widely accepted as a regulator for MMP‐2 and MMP‐9 . As expected, our result showed that IL‐17A up‐regulated the expressions of MMP‐9 and MMP‐2 in a time‐dependent pattern compared to the control group in U251 and U87 cells.…”

MicroRNAs Involved in Metastasis of Hepatocellular Carcinoma: Target Candidates, Functionality and Efficacy in Animal Models and Prognostic Relevance

“…miR-29a ( Figure 2A) promoted metastasis by silencing suppressor of cytokine signaling 1 (SOCS1), an inhibitor of metastatic signal transduction (52,53), due to methylation of its DNA, and subsequent activation of Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling (52). miR-29a directly targets ten eleven translocation enzymes (TET) which convert 5-methylcytosine to 5-hydroxy- methylcytosine, resulting in inhibition of SOCS1 promoter demethylation (52)(53)(54). miR-29a promotes proliferation and invasion of HCC cell lines SMMC-7721 and HCCLM3 and increases tumor growth and lung metastasis of orthotopically implanted HCCLM3 and SMMC-7721 HCC cells transfected with miR-29a (52).…”

“…miR-29a directly targets ten eleven translocation enzymes (TET) which convert 5-methylcytosine to 5-hydroxy- methylcytosine, resulting in inhibition of SOCS1 promoter demethylation (52)(53)(54). miR-29a promotes proliferation and invasion of HCC cell lines SMMC-7721 and HCCLM3 and increases tumor growth and lung metastasis of orthotopically implanted HCCLM3 and SMMC-7721 HCC cells transfected with miR-29a (52). miR-29a overexpression is correlated with poor clinical outcome in patients with HCC and inhibition of TET-SOCS mediated signaling in HCC tissues.…”

Crosstalk between microRNA expression and DNA methylation drive the hormone-dependent phenotype of breast cancer

“…In breast cancer, expression of miRNAs has been associated with clinical and molecular subtypes [10][11][12], progression [13][14][15], prognosis [16,17] and expression of oncogenes [18]. Importantly, miRNAs have been shown to regulate the expression of epigenetic regulators such as DNMTs and TETs [19,20]. We have previously shown how concerted alterations in copy number or promoter methylation affect miRNA expression in cis, resulting in up-regulation of oncogenic miRNAs and down-regulation of tumor-suppressor miRNAs [21].…”