Key Laboratory of Developmental Genes and Human Diseases

Nanjing, China

Key Laboratory of Developmental Genes and Human Diseases

Nanjing, China

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Fan H.,Key Laboratory of Developmental Genes and Human Diseases | Chen L.,University of Hong Kong | Chen L.,Sun Yat Sen University | Zhang F.,Key Laboratory of Developmental Genes and Human Diseases | And 10 more authors.
Oncogene | Year: 2012

DNA methyltransferase 3B (DNMT3B) mediates gene silencing via epigenetic mechanisms during hepatocellular carcinoma (HCC) progression. We aimed to identify novel targets of DNMT3B and their potential regulatory mechanisms in HCC. Metastasis suppressor 1 (MTSS1) was one of the DNMT3B targets and selected for further study. DNMT3B overexpression was detected in 81.25% of clinical HCC specimens and was negatively associated with MTSS1 in HCC cells and clinical samples. The underlying mechanism by which DNMT3B silences MTSS1 was studied using a combination of methylation-specific polymerase chain reaction (PCR) and bisulfite genome sequencing, chromatin immunoprecipitation-PCR and luciferase reporter assays. We found that the MTSS1 promoter region was sparsely methylated, and the methylation inhibitors failed to abolish DNMT3B-mediated MTSS1 silencing. DNMT3B protein bound directly to the 5′-flanking region (-865/-645) of the MTSS1 gene to inhibit its transcription. The functional role of MTSS1 was investigated using in vitro and in vivo tumorigenicity assays. As a result, MTSS1 exerted tumor suppressor effects and arrested cells in the G2/M phase, but not the G1/S phase of the cell cycle when it was depleted or overexpressed in HCC cells. Taken together, MTSS1, a novel target of DNMT3B, is repressed by DNMT3B via a DNA methylation-independent mechanism. MTSS1 was further characterized as a novel tumor suppressor gene in HCC. These findings highlight how DNMT3B regulates MTSS1, and such data may be useful for the development of new treatment options for HCC. © 2012 Macmillan Publishers Limited All rights reserved.


PubMed | Key Laboratory of Developmental Genes and Human Diseases
Type: Journal Article | Journal: Experimental and therapeutic medicine | Year: 2012

E-cadherin is a key cell adhesion molecule implicated in tumor suppression that is frequently altered in hepatocellular carcinoma (HCC), particularly in hepatitis B virus-related tumors. Here, we report that the epigenetic drugs 5-azacytidine and trichostatin A up-regulated E-cadherin expression in HCC cells. The depletion of DNMT1 restored E-cadherin expression via demethylation, whereas the depletion of DNMT3A or DNMT3B did not. Activated E-cadherin suppressed HCC cell colony formation. However, E-cadherin expression was repressed by HBx transfection due to the DNA methylation induced by the elevation of DNMT1 in the HCC cell lines. The present study indicates that E-cadherin expression is regulated by epigenetic agents in HCC cells, which suggests a schema for restoring E-cadherin by targeting its epigenetic mechanism.

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