ATM expression is attenuated by promoter hypermethylation in human ovarian endometriotic stromal cells

Abstract

A number of genes involved in the pathogenesis of endometriosis are silenced by the hypermethylation of their promoter regions. We assessed the effect and mechanism of the DNA demethylating agent 5-aza-2-deoxycytidine (5-aza-dC) (10 μM) on the cell cycle in human endometriotic cyst stromal cells (ECSCs) and normal endometrial stromal cells (NESCs) by flow cytometry. The DNA methylation status of G2/M checkpoint regulators were investigated by methylation-specific PCR. The expression of ataxia telangiectasia mutated (ATM) and the effect of 5-aza-dC on its expression were also evaluated by quantitative RT-PCR and western blotting analysis. 5-aza-dC treatment resulted in the cell cycle arrest of ECSCs at the G2/M phase. In contrast, 5-aza-dC did not affect the cell cycle of NESCs. The promoter region of the ATM gene was hypermethylated in ECSCs, but not in NESCs. ATM mRNA expression was attenuated in ECSCs compared to that in NESCs. Further, 5-aza-dC was found to restore ATM expression in ECSCs by its promoter demethylation. Our findings indicate that ATM promoter hypermethylation occurs in endometriosis, and that ATM silencing is involved in tumorigenesis during this disease; moreover, selective DNA demethylating agents and molecular target drugs against ATM silencing are promising for the treatment of endometriosis.

ATM-deficient lung, prostate and pancreatic cancer cells are acutely sensitive to the combination of olaparib and the ATR inhibitor AZD6738

“…Indeed, immunohistochemistry of ATM protein expression in lung adenocarcinoma revealed that over 40% had low protein expression, despite only 10% showing gene mutation 48 . In addition, ATM promoter methylation has been shown to lead to silencing in some cancer cells 49,50 . Therefore, it is possible that more patient samples may lack ATM expression or function than indicated by exome sequencing and that methods for assaying ATM protein expression and/or activity will be required for patient selection.…”

Differential DNA Methylation and Gene Expression Between ALV-J-Positive and ALV-J-Negative Chickens

“…SLC5A8 has been shown to be a tumor suppressor in lung tumor and silenced by promoter hypermethylation in the development of lung cancer (52). Several studies have reported that there are some genes with aberrant DNA methylation in promoter regions in endometriosis, such as HOXA10 (53) and ATM (54). Taken together, these reports reveal that DNA methylation is implicated in the development of disease.…”

ATM-deficient lung, prostate and pancreatic cancer cells are acutely sensitive to the combination of olaparib and the ATR inhibitor AZD6738

“…Indeed, immunohistochemistry of ATM protein expression in lung adenocarcinoma patient samples revealed that over 40% had low protein expression, despite only 10% showing gene mutation (Villaruz et al 2016). In addition, promoter methylation has been shown to lead to ATM gene silencing in some cancer cells (Hirakawa et al 2019;Kim et al 2002;Jette et al 2020). Therefore, it is possible that more patient samples may lack ATM expression or function than indicated by exome sequencing alone and that methods for assaying ATM protein expression and/or activity will be required for patient selection.…”