Dynamic Regulation of CYP19A1 Promoter Region under Control of CREB Family Members in Endometrial Tissues of Women...

Endometriosis is an estrogen-dependent disease. Cytochrome P450 aromatase which encoded by CYP19A1 is a key enzyme in the pathway of estrogen biosynthesis. cAMP response element (CRE) binding protein (CREB) and cAMP response element modulator (CREM), two members of the CREB family have important roles in the regulation of steroidogenic gene expression. CREB and CREM form homo and heterodimers for binding to the CRE sequence in the promoter of the CYP19A1 gene and regulate its expression. CREB regulated transcription coactivator 2 (CRTC2) is a CREB coactivator and regulates aromatase gene expression via binding to the CREB. Inducible cAMP early repressor (ICER) is one of CREM inhibitory isoforms that represses cAMP-induced transcription. Therefore, in this study, we decided to examine the expression levels of CREB, CREM, and CRTC2 genes and also the binding of ICER to the promoter II of the aromatase gene in endometriosis.

In this case-control study, ectopic and eutopic endometrial tissues of women with endometriosis and endometrial control samples were collected. Real-time polymerase chain reaction (PCR) technique was used for quantitative gene expression of CREB, CREM, and CRTC2. For protein-DNA interaction analysis, soluble chromatin was extracted, and chromatin immunoprecipitation (ChIP) coupled with real-time PCR was performed to quantify the binding of ICER to CYP19A1 promoter II.

Gene expression levels of CREB, CREM, and CRTC2 were significantly increased in ectopic lesions compared with control endometrial samples. In addition, the binding of ICER to CYP19A1 promoter II was significantly decreased in ectopic and eutopic samples compared to the controls.

The overexpression of CREB, CREM, and CRTC2 in the endometriotic tissue samples and decreased binding of ICER to the CYP19A1 prompter II in ectopic and eutopic samples may contribute to the pathogenesis of endometriosis via their regulatory role in the expression of estrogen biosynthesis enzymes.