Inhibition of Histone methyltransferase for fighting endometriosis

EZH2 may be an effective therapeutic target in endometriosis.

Key Points

Highlight:

• Inhibition of the histone methyltransferase EZH2 reduced H3K27me3 levels in the endometriotic cells specifically, and also reduced their migration, proliferation but not the invasion.

What’s done here:

• Characterize the expression levels of EZH2 in endometriotic tissues.
• Assess H3K27me3 enrichment in endometriosis candidate genes promoter regions.
• Determine if pharmacological inhibition of EZH2 impacts migration, proliferation, and invasion of endometriotic cells.

Key points:

• Endometriotic lesions had significantly higher EZH2α nuclear immunostaining levels compared to eutopic endometrium from controls.
• H3K27me3 was enriched within the promoter regions of several endometriosis candidate genes (e.g. ESR1, CDH1) in some endometriotic lesions.
• Inhibition of EZH2 reduced H3K27me3 levels in the endometriotic cells specifically, and also reduced migration, proliferation but not the invasion of endometriotic epithelial cells.

Limitations:

• More investigations regarding the role of EZH2 in invasion are needed.
• It would also be important to assess the effects of EZH2 inhibitor in other key cellular behaviors such as apoptosis, angiogenesis, and immune/inflammatory responses.
• Subsequent pre-clinical studies are required to determine the in vivo efficacy and safety of EZH2 inhibitors as promising non-hormonal therapeutic options for women with endometriosis.

Lay Summary

Although the histone methyltransferase EZH2 and its product H3K27me3 are well studied in cancer, little is known about their role and potential as therapeutic targets in endometriosis.

It has been previously reported that the endometriotic lesions are characterized by global enrichment of H3K27me3, suggesting that targeting EZH2 may be a promising option.

This Puerto-Rico-USA collaborative study found that endometriotic lesions had significantly higher EZH2α nuclear immunostaining levels compared to the eutopic endometrium from controls. In some endometriotic lesions, H3K27me3 was enriched within the promoter regions of endometriosis candidate genes including ESR1 and CDH1.

Furthermore, targeting EZH2 reduced H3K27me3 levels in the endometriotic cells specifically, and also reduced migration, proliferation but not the invasion of endometriotic epithelial cells. The authors suggest that EZH2 may be an effective therapeutic target since blocking this enzyme can impact several of the underlying cellular behaviors activated in endometriosis.

However, it is important to investigate the role of EZH2 on invasion and effects of EZH2 inhibitor in other key cellular behaviors to better clarify the issue.

Lastly, subsequent pre-clinical studies are required to determine the in-vivo efficacy and safety of EZH2 inhibitors as promising non-hormonal therapeutic options for women with endometriosis.

Research Source: https://www.ncbi.nlm.nih.gov/pubmed/29408993