TGF-β: friend or foe? The role of TGF-β/SMAD signaling in epigenetic silencing of ovarian cancer and its implication in epigenetic therapy

Importance of the field: The TGF-beta signaling pathway plays an important role in regulating numerous cellular processes including growth inhibition of ovarian surface epithelial (OSE) cells. However, epithelial ovarian cancer is refractory to the inhibitory functions of TGF-beta, and yet TGF-beta induces metastasis or epithelial--mesenchymal transition (EMT) in advanced ovarian cancer. How TGF-beta plays a certain role in one cell but a different role in its malignant counterpart is not fully understood. Areas covered in this review: The role of TGF-beta/SMAD signaling both in normal OSE cells and ovarian cancer as well as how dysregulation of this signaling pathway leads to epigenetic silencing of its downstream targets in ovarian neoplasias are reviewed. The therapeutic implication of this signaling pathway in epigenetic therapy of ovarian cancer are also discussed. What the reader will gain: The reader will gain insight on how dysregulation of TGF-beta signaling alters promoter methylation and histone modifications of TGF-beta downstream targets in ovarian cancer. Take home message: Disruption of TGF-beta/SMAD signaling leads to epigenetic silencing of its target genes transiently through histone modifications but permanently by promoter hypermethylation. Targeting the TGF-beta signaling pathway may be a novel therapeutic strategy in ovarian cancer.