PCAF Impairs Endometrial Receptivity and Embryo Implantation by Down-Regulating β3-Integrin Expression via HOXA10 Acetylation

Background: Homeobox A10 (HOXA10), a key transcription factor, plays a critical role in endometrial receptivity by regulating the expression of downstream target genes, such as beta 3-integrin (ITGB3), but little is understood about the mechanisms of the posttranslational modification of HOXA10 during embryo implantation. Objective: The aim of this study was to assess the effect of HOXA10 acetylation by p300/CREB-binding protein-associated factor (PCAF) in the embryo implantation process. Methods: The association of HOXA10 with PCAF was detected by coimmunoprecipitation, Western blotting, and confocal immunofluorescent assays. A luciferase reporter assay, Western blotting, quantitative real-time PCR, and chromatin immunoprecipitation techniques were used to determine the effect of PCAF on HOXA10 protein stability and the HOXA10-mediated regulation of ITGB3 expression. HOXA10-PCAF association on embryo implantation was evaluated using a BeWo spheroid attachment assay. PCAF expression in the eutopic endometrium of women with endometriosis and fertile controls was measured by Western blotting technique. Results: PCAF was identified as an HOXA10-interacting protein and inhibited HOXA10-mediated ITGB3 transcription via acetylating HOXA10 at K338 and K339. Overexpressing or knocking down PCAF in Ishikawa cells showed that PCAF not only down-regulated HOXA10-mediated ITGB3 protein expression but also diminished HOXA10-mediated embryo adhesiveness by acetylating HOXA10 (P < .05). Furthermore, we found aberrantly high PCAF expression in the eutopic endometrium of women with a diagnosis of endometriosis compared with the fertile controls (P < .05). Conclusions: These observations demonstrate that 1) HOXA10 associates with and is acetylated by PCAF at lysines K338 and K339 in Ishikawa cells and 2) HOXA10-PCAF association impairs embryo implantation by inhibiting ITGB3 protein expression in endometrial epithelial cells.