Nuclear receptor co-regulator Krüppel-like factor 9 and prohibitin 2 expression in estrogen-induced epithelial cell proliferation in the mouse uterus

Estrogen, acting through its cognate receptor estrogen receptor-α (ESR1), is a critical regulator of uterine endometrial epithelial proliferation. Although the dynamic communication between endometrial stromal (ST) and epithelial cells is considered to be an important component in this process, key molecular players in particular compartments remain poorly defined. Here, we used mice null for Krüppel-like factor 9 (KLF9) to evaluate the contribution of this nuclear protein in ST–epithelial interactions underlying proliferative effects of estrogen. We found that in ovariectomized mice administered estradiol-17β (E2) for 24 h,Klf9null mutation resulted in lack of E2-induced proliferative response in all endometrial compartments. We demonstrated a negative association betweenKlf9expression and nuclear levels of ESR1 transcriptional corepressor prohibitin (PHB) 2 in uterine ST and epithelial cells of E2-treated wild-type (WT) andKlf9null mice. In early pregnancy uteri of WT mice, the temporal pattern ofKlf9transcript levels was inversely associated with that ofPhb2. Deletion ofKlf9up-regulated uterinePhb2expression and increased PHB2 nuclear localization in endometrial ST and epithelial cells, with no effects on the expression of the relatedPhb1. In the human endometrial ST cell line treated with E2for 24 h,Klf9siRNA targeting augmented PHB2 transcript and increased nuclear PHB2 protein levels, albeit this effect was not to the extent seenin vivowithKlf9null mutants. Our findings suggest a novel mechanism for control of estrogen-induced luminal epithelial proliferation involving ST KLF9 regulation of paracrine factor(s) to repress epithelial expression of corepressor PHB2.