The PES1/FOXM1 heterodimer suppresses TCF21 and ER expression in ovarian endometriosis

Transcription factor 21 (TCF21) and estrogen receptor beta (ER beta, encoded by ESR2) are highly expressed in endometriotic stromal cells (ESCs) and contribute to the pathogenesis of endometriosis. However, the exploration of TCF21 and ER beta expression regulation at the molecular level remains limited. Here, by using bioinformatics analysis and experimental verification, we identified PES1, also known as Pescadillo, as a negative regulator in the development of endometriosis that downregulates TCF21 and ER beta expression in ESCs. PES1 overexpression regulated critical biological processes involved in endometriosis development, such as invasion and apoptosis. A coimmunoprecipitation assay showed that PES1 could form a complex with Forkhead box M1 (FOXM1). Further analyses elucidated that siPES1 in ectopic lesions decreased the stability of FOXM1 protein and reduced the binding activities of FOXM1 to TCF21 and ESR2 promoters, thus weakening the transcriptional inhibition of TCF21 and ER beta by FOXM1. Moreover, in an endometriosis mouse model, overexpressing PES1 effectively reduced the growth of ectopic lesions and suppressed TCF21 and ER beta expression, which suggests a promising therapeutic strategy for endometriosis. Collectively, our results indicate that the loss of PES1 in ectopic lesions contributes to endometriosis progression by upregulating ER beta and TCF21 expression through heterodimer formation with FOXM1. Moreover, targeting PES1 could serve as a treatment method for endometriosis. Transcription factor 21 (TCF21) and estrogen receptor beta (ER beta, encoded by ESR2) are the key factors in the pathogenesis of endometriosis, but their co-regulation mechanism is still unknown. We discovered for the first time that PES1 is downregulated in ectopic lesions. PES1 reduces the stability of the FOXM1 protein and weakens the transcriptional inhibition of ER beta and TCF21 by FOXM1. Moreover, overexpression of PES1 effectively suppressed the growth of ectopic lesions in mice. Altogether, these results suggest that PES1 has therapeutic potential for endometriosis.image