| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 2569130 | Toxicology and Applied Pharmacology | 2012 | 10 Pages |
Hepatic stellate cell (HSC) activation is an essential event during liver fibrogenesis. Phosphatase and tension homolog deleted on chromosome 10 (PTEN), a tumor suppressor, is a negative regulator of this process. PTEN promoter hypermethylation is a major epigenetic silencing mechanism in tumors. The present study aimed to investigate whether PTEN promoter methylation was involved in HSC activation and liver fibrosis. Treatment of activated HSCs with the DNA methylation inhibitor 5-aza-2′-deoxycytidine (5-azadC) decreased aberrant hypermethylation of the PTEN gene promoter and prevented the loss of PTEN expression that occurred during HSC activation. Silencing DNA methyltransferase 1 (DNMT1) gene also decreased the PTEN gene promoter methylation and upregulated the PTEN gene expression in activated HSC-T6 cells. In addition, knockdown of DNMT1 inhibited the activation of both ERK and AKT pathways in HSC-T6 cells. These results suggest that DNMT1-mediated PTEN hypermethylation caused the loss of PTEN expression, followed by the activation of the PI3K/AKT and ERK pathways, resulting in HSC activation.
Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (83 K)Download as PowerPoint slideHighlights► PTEN methylation status and loss of PTEN expression ► DNMT1 mediated PTEN hypermethylation. ► Hypermethylation of PTEN contributes to the activation of ERK and AKT pathways.
