Functional analysis of glycodelin induced by HDACI in endometrial glandular epithelium.

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Human uterine endometrium repeats proliferation, differentiation (decidualization) and tissue breakdown during the menstrual period. Histone reversible acetylation, regulated by histone acetylase and deacetylase, govern gene transcription. To develop new strategy of treatment for impairment of implantation, we analyze the possibility of histone deacetylase inhibitors (HDACI) as a differentiation inducer of human endometrium, instead of ovarian steroid hormones.We analyzed the effect of ovarian steroid hormones or HDACI onto Ishikawa cells (human adenocarcinoma cell line), which is used as a model of human endometrial glandular epithelium. In a similar way to ovarian steroid hormones, HDACI affected the following function in Ishikawa cells.1)HDACI induced the both mRNA and protein expression of glycodelin, which is highly expressed in differentiated (luteal-phase) endometrial gland, via glycodelin promoter region.2)Flattened and wide-spread morphological changes of cells were shown by HDACI.3)HDACI enhanced the production of glycogen.4)HDACI up-regulated single cell motility, analyzed with trans-well cell migration assay.5)HDACI enhanced collective cell motility, tested with wound healing assay.6)Glycodelin permanent expression clones showed accelerated single and collective cell migration.7)Glycodelin gene silencing by siRNA abolished the effect by HDACI, mentioned above.Taken together, HDACI have a potential to induce both differentiation and migration of endometrial cells through up-regulation of glycodelin, providing a clue for a possible therapeutic strategy to modulate endometrial function by targeting glycodelin.