Regulation of SIRT1 determines initial step of endometrial receptivity by controlling E-cadherin expression.
Sirtuin 1 (SIRT1), originally found as a class III histone deacetylase, is a principal modulator of pathways downstream of calorie restriction, and the activation of SIRT1 ameliorates glucose homeostasis and insulin sensitivity. We examined the role of SIRT1 in the regulation of uterine receptivity using Ishikawa and RL95-2 endometrial carcinoma cell lines. Exogenous expression of SIRT1 significantly enhanced E-cadherin expression, while small interfering RNA-mediated depletion of endogenous SIRT1 resulted in a significant reduction of E-cadherin expression. A SIRT1 activator resveratrol elevated E-cadherin expression in a dose dependent manner, while SIRT1 repressors nicotinamide and sirtinol exhibited a dose dependent reduction of E-cadherin expression. We also showed that both forced expression of SIRT1 and activation of SIRT1 promote E-cadherin-driven reporter gene constructs, and SIRT1 is localized at E-cadherin promoter containing E-box elements in Ishikawa cells. Using an in vitro model of embryo implantation, we demonstrate that exogenous expression of SIRT1 and stimulation of SIRT1 activity resulted in the Ishikawa cell line becoming receptive to JAR cell spheroid attachment. Furthermore, resveratrol enhanced E-cadherin and Glycodelin protein expression at sites of intercellular contact, suggesting an additive role of resveratrol in promoting implantation. The initial step of human reproduction depends on the capacity of an embryo to attach and implant into the endometrial wall, and these results revealed the novel mechanism that activation and increased expression of SIRT1 play an important role in uterine receptivity.
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
Akira
A
Shirane
Osamu
O
Wada-Hiraike
Michihiro
M
Tanikawa
Takayuki
T
Seiki
Haruko
H
Hiraike
Yuichiro
Y
Miyamoto
Kenbun
K
Sone
Mana
M
Hirano
Hajime
H
Oishi
Katsutoshi
K
Oda
Kei
K
Kawana
Shunsuke
S
Nakagawa
Yutaka
Y
Osuga
Tomoyuki
T
Fujii
Tetsu
T
Yano
Shiro
S
Kozuma
Yuji
Y
Taketani
D000199:Actins / Q000378:metabolism; D015820:Cadherins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D010064:Embryo Implantation; D004717:Endometrium / Q000378:metabolism / Q000502:physiology*; D005260:Female; D000071816:Glycodelin; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D011257:Pregnancy Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin
D000199:Actins; C107489:BIRC5 protein, human; D015820:Cadherins; D000071816:Glycodelin; D006023:Glycoproteins; D051034:Inhibitor of Apoptosis Proteins; C045246:PAEP protein, human; D011257:Pregnancy Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; C447939:SIRT1 protein, human; D056564:Sirtuin 1