The Role of SMAD7 in the Epigenetic Regulation of TGF-β Targets in the Metastasis of Ovarian Cancer.

Abstract

The role of TGF-β signaling in the epigenetic modifications involved in ovarian cancer is not fully understood. This study investigated the relationship between TGF-β signaling, epigenetic modifications, and cellular behaviors in ovarian cancer. We found that E-cadherin, a key cell adhesion molecule, underwent epigenetic silencing via promoter DNA hypermethylation in ovarian cancer cell lines and that this was accompanied by the upregulation of vimentin, which is indicative of a mesenchymal and invasive phenotype. DNA-demethylating agents restored E-cadherin expression, which suggests that TGF-β signaling mediates this epigenetic silencing. Overexpression of SMAD7, an inhibitory component of TGF-β signaling, reversed E-cadherin silencing, which suggests a role of SMAD7 in modulating the epigenetic status. Functionally, SMAD7 overexpression inhibited the migration and invasion in ovarian cancer cells, which suggests its therapeutic potential for suppressing metastasis. Clinically, ovarian cancer patients with high SMAD7 expression had significantly longer disease-free survival. Mechanistically, SMAD7 overexpression decreased the acetylation of H3K9 and the binding of the transcriptional repressor TWIST1 at the E-cadherin promoter, which promoted its demethylation and reactivation. Disruption of TGF-β signaling upregulated SMAD4 target genes, which are silenced by epigenetic mechanisms, a finding that suggests broader therapeutic implications. Overall, our results provide insights into the role of TGF-β-mediated epigenetic regulation in ovarian cancer metastasis and underscore the therapeutic potential of targeting TGF-β signaling and its downstream effectors. Further research is needed to elucidate the underlying mechanisms and validate these therapeutic strategies.