Effect of the histone deacetylase inhibitor Romidepsin on proliferation and migration of human epithelial endometriotic cells and on expression of E-cadherin and matrix metalloproteinase-2

Abstract

Endometriosis is characterized by the ectopic growth of endometrial tissue. Endometriosis is a chronic disorder affecting about 10-15% of reproductive-aged women. It can be associated with non-cyclic pelvic pain, infertility, dysmenorrhoea, and dyspareunia, and it often has a negative impact on life quality of the concerned women. Although endometriosis is a benign disorder it seems to share some characteristics with cancers. These include increased growth and survival, invasion, and angiogenesis. Currently available medical treatments are essentially aim at downregulating ovarian function, thereby reducing the amount of estrogens in order to inhibit growth and proliferation, or at inhibiting the invasive and the angiogenic potential of cells in endometriotic lesions. Surgery is also applied to treat endometriosis.
Recent studies propose a role of epigenetic alterations such as histone modifications and DNA methylation in the pathogenesis of endometriosis. Histone deacetylation (hypoacetylation) is produced by histone deacetylases (HDACs) and is a modification belived to result in gene silencing, i.e. inhibition of gene transcription. HDAC-inhibitors (HDAC-i) are a novel class of epigenetic acting drugs. HDAC-i cause hyperacetylation of histones, resulting in reactivation of silenced genes. HDAC-i are mainly studied in cancer biology as potential anticancer agents but recent studies suggest a potential use against endometriosis.
The aim of this study was to determine in 11z epithelial endometriotic cells the effects of the HDAC-i Romidepsin (also known as FK-228, depsipeptide) on the expression of p21, E-cadherin, and MMP-2, and on the survival and migratory behavior of these cells. p21 is an anti-proliferative protein involved in the cell cycle, E-cadherin is a cell-cell-adhesion protein involved in cell migration, and MMP-2 is a matrix metalloproteinease involved in extracellular matrix degradation and invasion. Cell survival was determined by the MTT-assay, protein expression and histone acetylation were investigated by gelelectrophoresis and Western blot analysis of whole cell lysates, and the migratory behavior of the cells was assessed by the “wound healing” assay.
The results showed that Romidepsin produced the acetylation of the histone H3, the upregulation of p21, and the upregulation of E-cadherin. Romidepsin also inhibited the survival and the migration of 11z cells, indicating that Romidepsin, as an epigenetically acting compound, negatively affects two important processes of endometriosis. It therefore may be concluded that Romidepsin is a compound which should be further studied as a potential candidate compound to encounter endometriosis. This study also supports the role of epigenetic alterations in endometriosis and may be a valuable contribution to the field of endometriosis in the context of the development of novel treatment option against this disorder.