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Submitted on March 28, 2005
Accepted on August 18, 2005
Department of Obstetrics and Gynecology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
* To whom correspondence should be addressed. E-mail: tetsuo{at}sc.itc.keio.ac.jp.
Histone reversible acetylation, which is controlled by histone acetyltransferases and deacetylases, plays a fundamental role in gene transcription. Histone deacetylase inhibitors (HDACIs) such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) have been characterized not only as anti-cancer drugs but also as cytodifferentiation-inducing agents. In human endometrium, postovulatory production of progesterone directs estrogen-primed endometrial glandular cells to differentiate and thereby produce a number of unique bioactive substances including glycodelin that are critical for implantation at the secretory phase of the menstrual cycle. We here show that TSA and SAHA belonging to the hydroxamic acid group of HDACIs can induce the phenotype of a human endometrial adenocarcinoma cell line Ishikawa (originally derived from the glandular component of the endometrium) to differentiate to closely resemble normal endometrial epithelium in a time- and dose-dependent manner, as determined by morphological changes, synthesis of glycogen, and expression of secretory phase-specific proteins including glycodelin. The proliferation- and differentiation-modulating effects elicited by TSA and SAHA at their optimal concentrations were comparable or more potent than those exerted by combined treatment with progesterone and estradiol. Furthermore, the gene silencing of glycodelin by small interference RNA resulted in the blockade of HDACI-induced differentiation in Ishikawa cells, suggesting the requirement of glycodelin for the endometrial epithelial differentiation. Our results collectively indicate that the TSA and SAHA are potent differentiation-inducers for endometrial glandular cells, providing a clue for a possible therapeutic strategy to modulate endometrial function by targeting glycodelin.
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