The Role of EZH2 as an Epigenetic Switch of the TGF-Beta Targets in Regulating EMT and Its Therapeutic Implication in Ovarian Cancer
Description: The TGF-p/SMAD signaling pathway plays an important role in controlling growth inhibition as well as epithelial-mesenchymal transition (EMT) of ovarian cancer. Previous studies demonstrated that normal ovarian surface epithelial cells and early ovarian cancer are sensitive to TGF-P-mediated growth inhibition. On the contrary, advanced staged ovarian cancer are refractory to this growth inhibition, and yet TGF-P has been shown to further promote EMT in this sub-group of ovarian cancer. However the mechanism of this transition in ovarian cancer is poorly understood. We hypothesize that the polycomb repressor, EZH2 may act as an epigenetic switch of the TGF-p/SMAD targets in regulating the function of TGF-P in ovarian cancer. Targeted inhibition of EZH2 and the TGF-P signaling may reverse the epigenetic status of these genes and subsequently inhibit EMT in ovarian cancer. Our preliminary result demonstrated that a sub-group of our previous identified TGF-P regulated targets in IOSE cells are also targets of EZH2 in human ES cells as demonstrated in ENCODE ChlP-Seq database. Massively parallel sequencing (MethylCap-Seq) revealed that portion of these TGF-P/EZH2 targets are methylated in CP70 ovarian cancer cells. Interestingly, knockdown of SMAD4 altered the methylation status of these TGF-P/EZH2 targets in this cell. Results from combined bisulphite pyrosequencing and treatment of epigenetic drugs including EZH2 inhibitor (GSK343) suggested that one of the targets, LTBP2 are epigenetically silenced by DNA methylation and H3K27me3. Importantly, knockdown of SMAD4 or treatment of GSK343 inhibited the TGF-P induced invasion of CP70 cells. In this regard, we propose to perform experiments with the following specific aims: 1. Identify the EZH2 targets and their chromatin landscaping in ovarian cancer by massively parallel sequencing; 2. Determine the role of epigenetic machinery in the transcriptional regulation of the TGF-P/EZH2 targets in related to TGF-P mediated EMT in ovarian cancer; 3. Determine the biological and clinical significance of the TGF-P/EZH2 targets in ovarian cancer patients (around 100 cancer, 20 benign and 5 normal ovarian tissue) and in an animal model; 4. Investigate the therapeutic potential of using EZH2 inhibitor in the treatment of ovarian cancer. We anticipate that a panel of TGF-P/EZH2 targets that are important for TGF-P mediated EMT in ovarian cancer will be identified. The clinical potential of using those targets as prognostic marker will be assessed. Importantly, the therapeutic value of using EZH2 inhibitor as novel treatment strategy in ovarian cancer will be evaluated.
Amount: TWD 1,190,000
Funding type: research
Funder scheme: 學術補助
Investigator: 陳永恩
Institution: 國立中正大學生命科學系
Funded outputs count: 5
Funder award ID: MOST103-2320-B194-002
OpenAlex ID: G686282909