FKBP4 is regulated by HOXA10 during decidualization and in endometriosis

Abstract

FKBP4 (FKBP52) and FKBP5 (FKBP51) are progestin receptor (PR) co-chaperone proteins that enhance and inhibit, respectively, progestin-mediated transcription by PR. Here, we examinedFKBP4andFKBP5expression in the eutopic endometrium of fertile women with endometriosis and effects of FKBP4 and FKBP5 on the decidualization of human endometrial stromal cells (HESCs), and assessed HOXA10 regulation of FKBP4. Expression ofFKBP4mRNA was increased in the late proliferative phase and remained elevated throughout the secretory phase.FKBP5expression was low and remained constant throughout the menstrual cycle. Compared with controls,FKBP4mRNA expression was decreased in the endometrium of women with endometriosis, whereas no significant endometriosis-related change was seen forFKBP5. Cultured HESCs were treated with eitherFKBP4orFKBP5siRNA and then decidualized by incubation with progesterone (P4) and 8-bromoadenosine cAMP. Treatment of HESCs withFKBP4siRNA resulted in 60% lowerIGFBP1expression. In contrast, incubation withFKBP5siRNA did not significantly decreaseIGFBP1expression duringin vitrodecidualization.HOXA10andFKBP4expression increased in parallel duringin vitrodecidualization. In HESCs, overexpressed HOXA10 enhanced FKBP4 mRNA and protein levels, whereas HOXA10 knockdown decreased FKBP4 mRNA and protein levels compared with controls. Similarly, duringin vitrodecidualization,FKBP4expression was decreased in HOXA10-silenced cells. EnhancedHOXA10expression in HESCs elicits a decidualization mediating increase inFKBP4expression. The findings are consistent with the observation that women with endometriosis have diminishedFKBP4expression leading to impaired decidualization and infertility. The P4resistance seen in endometriosis may be mediated through HOXA10-regulatedFKBP4expression.