TET enzymes and 5hmC epigenetic mark: new key players in carcinogenesis and progression in gynecological cancers.

DNA methylation is an epigenetic mechanism involving the transfer of a methyl group onto the C5 position of the cytosine to form 5-methylcytosine (5mC). In general, DNA methylation in cancer is associated with the repression of the expression of tumor suppressor genes (TSG) and the demethylation with the overexpression of oncogenes. DNA methylation was considered a stable modification for a long time, but in 2009, it was reported that DNA methylation is a dynamic modification. The Ten-Eleven-Translocations (TET) enzymes include TET1, TET2, and TET3 and participate in DNA demethylation through the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC). The 5hmC oxidates to 5-formylcytosine (5fC) and 5-carboxylcitosine (5caC), which are replaced by unmodified cytosines via Thymine-DNA Glycosylase (TDG). Several studies have shown that the expression of TET proteins and 5hmC levels are deregulated in gynecological cancers, such as cervical (CC), endometrial (EC), and ovarian (OC) cancers. In addition, the molecular mechanisms involved in this deregulation have been reported, as well as their potential role as biomarkers in these types of cancers. This review shows the state-of-art TET enzymes and the 5hmC epigenetic mark in CC, EC, and OC.

Use of coumarins as complementary medicine with an integrative approach against cervical cancer: background and mechanisms of action.

Cervical cancer is characterized by the cellular transformation caused by Human Papillomavirus (HPV), favoring cell proliferation, migration, invasion, and metastasis. Cervical cancer is conventionally treated with radiation therapy, and chemotherapy focused on the destruction of tumor cells. However, chemoresistance and low selectivity between tumor and non-tumor cells have been reported, causing side effects in patients. Metabolites of natural origin have shown selectivity against tumor cells, suggesting their use for reducing the side effects caused by drugs used in conventional therapy. Among these compounds, several natural coumarins stand out, such as auraptene, scopoletin, osthole, and praeruptorin, of which antiproliferative, anti-migratory, and anti-invasive activity have been reported. Auraptene, scopoletin, osthole, and praeruptorin show a cytotoxic or antiproliferative effect on cervical tumor cells, arresting the cell cycle by inducing the overexpression of negative regulators of the cell cycle, or inducing cell death by increasing the expression of pro-apoptotic proteins and decreasing that of anti-apoptotic proteins. On the other hand, auraptene, scopoletin, and praeruptorin inhibit the capacity for migration, invasion, and metastasis of cervical tumor cells, mainly by inhibiting the expression and activity of matrix metalloproteinase-2 and -9. The PI3K/Akt signal pathway appears to be central to the anti-tumor activity of the coumarins analyzed in this review. In addition, auraptene, osthole, and praeruptorin are useful in sensitizing tumor cells to radiotherapy or chemotherapeutic molecules, such as FOLFOX, cisplatin, or DOX. Coumarins offer an excellent possibility for developing new drugs as complementary medicine with an integrative approach against cervical cancer.