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Hum. Reprod. Advance Access originally published online on August 24, 2007
Human Reproduction 2007 22(10):2615-2622; doi:10.1093/humrep/dem263
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© The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Histone deacetylase inhibitor-induced glycodelin enhances the initial step of implantation

Hiroshi Uchida1, Tetsuo Maruyama, Kuniaki Ohta, Masanori Ono, Toru Arase, Maki Kagami, Hideyuki Oda, Takashi Kajitani, Hironori Asada and Yasunori Yoshimura

Department of Obstetrics and Gynecology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan

1 Correspondence address. Tel: +81-3-3353-1211 (ext. 63401); Fax: +81-3-3226-1667; E-Mail: uchida{at}sc.itc.keio.ac.jp

BACKGROUND: The complex molecular pathways governing implantation are unclear and ethical limitations limit studies in humans. Reversible histone acetylation regulates gene transcription and histone deacetylase inhibitors (HDACI) induce specific genes. Suberoylanilide hydroxamic acid (SAHA), a HDACI recently approved as an anti-cancer drug, induces the morphological and functional differentiation of human endometrial gland cells through up-regulation of glycodelin, a secretory phase dominant protein.

METHODS: We investigated whether SAHA improves implantation in an in vitro implantation assay using the human endometrial adenocarcinoma cell line, Ishikawa and the choriocarcinoma cell line, JAR.

RESULTS: In an in vitro implantation assay, JAR spheroids attached and adhered to Ishikawa cells in a time dependent manner. Glycodelin induction, following treatment with ovarian steroid hormones or SAHA, enhanced implantation. The improvement in implantation was also obtained when glycodelin was overexpressed without stimulation and was almost completely abrogated by glycodelin gene silencing.

CONCLUSIONS: This study demonstrates that glycodelin is a key regulatory protein of implantation and suggests that SAHA may have a capacity to supplant steroid derivatives in the treatment of infertility.

Key words: glycodelin/histone deacetylase inhibitor/implantation/SAHA

Submitted on May 9, 2007; resubmitted on June 8, 2007; accepted on June 19, 2007.


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