A higher degree of expression of DNA methyl transferase 1 in cervical cancer is associated with poor survival outcome

Abstract

BackgroundEven though novel therapies based on aberrant DNA methylation could be of particular importance for the treatment of cervical cancer (CC) because the oncoproteins E6/E7 of high-risk human papillomaviruses, the causative agents for developing CC, have the capacity to bind and upregulate DNA methyltransferases (DNMTs), to our knowledge, no previous studies have evaluated the expression of this enzyme in CC in relation to survival outcomes. The purpose of the study was to evaluate the expression of DNMT1 in CC and its association with survival outcomes.MethodsThe study population consisted of 76 women treated for primary CC and followed up by the University of Alabama at Birmingham (UAB) cancer registry. The expression of DNMT1 was examined using immunohistochemistry, and the degree of expression of DNMT1 was expressed as a percentage of cells positive for DNMT1 and its intensity. Cox proportional hazards model was used to assess the relationship between the degree of expression of DNMT1 and overall survival after adjusting for relevant covariates.ResultsThe expression of DNMT1 was significantly higher in CC cells compared to that in the normal cervical epithelium. A higher percentage of cells positive for DNMT1 and a higher intensity score for DNMT1 were significantly associated with poor survival outcome (hazard ratio [HR] =4.3, P=0.03 and HR =4.9, P=0.02, respectively).ConclusionOur findings suggested that the degree of expression of DNMT1 could be considered as a target in the epigenetic treatment of CC. Replication of our results in other study populations with CC could create the opportunity of using DNMT inhibitors to treat CC.

Genistein Modulates Signaling Pathways and Targets Several Epigenetic Markers in HeLa Cells

“…DNMT family of enzymes mediate methylation of DNA and are crucial players in epigenetic modification. Overexpression of DNMT1, 3A and 3B has been reported in cervical cancer cells and is associated with disease progression [30]. DNMT1, 3A and 3B expression were downregulated marking a possible decrease in functional consequence ( Figure 2).…”

Epigenetic Dysregulation at the Crossroad of Women’s Cancer

“…For example, HPV-E7 is known to regulate the expression, binding, and activity of DNMT1 [243,244,245]. In general, increased levels of DNMT1 in cervical tumors have been linked with a poor outcome [246], due to silencing of tumor suppressor genes. For example, E6 and E7 proteins stimulate the expression of DNMT1 via pRB and p53 pathways, respectively [243,244,245].…”

DNA methyltransferases in virus‐associated cancers

“…Cancer of cervix is known as the third most prevalent diagnosed cancer and one of the major causes of cancer death in women worldwide. 17,18 The high-risk human papilloma viruses 16 and 18 (HR-HPVs) are considered as a well-established cause of cervical cancer. 19,20 E6 and E7 are two proteins with oncogenic properties in HR-HPVs.…”