Michael W. Y. Chan

Wogonin Inhibits Ovarian Cancer by Activating the AMPK‐TET2‐5hmC Axis

ABSTRACTOvarian cancer is one of the most common gynecologic cancers. In the quest for effective anti‐cancer agents, this study explores the effects of wogonin, a naturally occurring flavonoid, on the viability and migration of A2780 and Kuramochi ovarian cancer cells. A2780 and Kuramochi human ovarian cancer cell lines were utilized. Cytotoxicity and migration were evaluated using the CCK8 assay and the wound‐healing assay, respectively. The effect of wogonin on the growth of A2780 ovarian cancer cells in vivo was assessed using a nude mouse model. The phosphorylation and half‐life of AMPK were determined by western blot analysis. The level of 5hmC was assessed using dot blot analysis. The impact of wogonin on gene expression was examined through RNA‐Seq. Our results show that wogonin not only impedes cancer cell growth and mobility both in vitro and in vivo but also significantly increases the cytotoxicity of cisplatin. Investigations of the mechanism underlying these effects reveal that wogonin suppresses genes associated with cell proliferation and the EMT and upregulates metabolic pathways, particularly the AMPK signaling pathway, which is crucial for increasing 5hmC levels. These results indicate that wogonin promotes DNA demethylation by stabilizing TET2. In conclusion, our findings highlight not only the therapeutic potential of wogonin but also its preventative capability against ovarian cancer in individuals with metabolic disorders, such as diabetes, who are at increased risk of ovarian cancer.

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

ABSTRACTThe 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.

Interplay between ceRNA and Epigenetic Control of microRNA: Modelling Approaches with Application to the Role of Estrogen in Ovarian Cancer

MicroRNAs (miRNAs) play an important role in gene regulation by degradation or translational inhibition of the targeted mRNAs. It has been experimentally shown that the way miRNAs interact with their targets can be used to explain the indirect interactions among their targets, i.e., competing endogenous RNA (ceRNA). However, whether the protein translated from the targeted mRNAs can play any role in this ceRNA network has not been explored. Here we propose a deterministic model to demonstrate that in a network of one miRNA interacting with multiple-targeted mRNAs, the competition between miRNA-targeted mRNAs is not sufficient for the significant change of those targeted mRNA levels, while dramatic changes of these miRNA-targeted mRNAs require transcriptional inhibition of miRNA by its target proteins. When applied to estrogen receptor signaling pathways, the miR-193a targets E2F6 (a target of estrogen receptor), c-KIT (a marker for cancer stemness), and PBX1 (a transcriptional activator for immunosuppressive cytokine, IL-10) in ovarian cancer, such that epigenetic silencing of miR-193a by E2F6 protein is required for the significant change of c-KIT and PBX1 mRNA level for cancer stemness and immunoevasion, respectively, in ovarian cancer carcinogenesis