SOX4 facilitates PGR protein stability and FOXO1 expression conducive for human endometrial decidualization

The establishment of receptive endometrium in human necessitates appropriate decidualization of stromal cells, which involves steroids regulated periodic transformation of endometrial stromal cells during menstrual cycle. Insufficient decidualization of endometrium contributes to not only the failure of embryo implantation and unexplained infertility, but also the occurrence of recurrent spontaneous abortion, intrauterine growth retardation, preeclampsia, and other clinical gynecological diseases. However, the potential molecular regulatory mechanism underlying the initiation and maintenance of decidualization in humans is yet to be fully elucidated. In this investigation, we document that SOX4 is a key regulator of human endometrial stromal cells (hESCs) decidualization by directly regulating PRL and FOXO1 expression as revealed by whole genomic binding of SOX4 assay and RNA-Seq. Besides, our immunoprecipitation and mass spectrometry results unravel that SOX4 modulates progesterone receptor (PGR) stability through repressing E3 ubiquitin ligase HERC4 mediated degradation. More importantly, we provide evidence that dysregulated SOX4-HERC4-PGR axis is a potential cause of defective decidualization and recurrent implantation failure (RIF) in IVF patients. In summary, this study evidences that SOX4 is a new and critical regulator for human endometrial decidualization, and provides insightful information for the pathology of decidualization-related infertility and will pave the way for pregnancy improvement.