Uncovering a New Molecular Driver in Endometriosis

Molecular Insights: SOX18 Fuels Endometriosis via OTUB1 and Hippo/YAP1 Signaling

Key Points

Highlights: 

• SOX18 promotes endometriosis progression by driving OTUB1 transcription and stabilizing YAP1 through the Hippo signaling pathway.
• This newly identified axis (SOX18–OTUB1–YAP1) links transcriptional regulation to cellular proliferation, migration, invasion, and epithelial–mesenchymal transition in endometriosis.

Importance:

• The findings provide mechanistic insight into endometriosis pathogenesis and highlight SOX18 as a potential biomarker and therapeutic target.
• Targeting this molecular axis could open avenues for novel non-hormonal and pathway-specific therapies, urgently needed for patients with refractory disease.

What’s done here:

• A series of in vitro experiments on Ishikawa cells and in vivo studies on mouse model were performed to investigate the role of SOX18 in endometriosis on proliferation, migration, invasion, and epithelial–mesenchymal transition.
• Ectopic endometrium samples confirmed endometriosis (n=9) and control eutopic endometrium samples (n=18) without evidence of endometriosis were used for immunohistochemistry to detect SOX18 expression.
• Disease progression in mice was evaluated to confirm translational relevance.

Key results:

• SOX18 overexpression enhanced proliferation, migration, invasion, and induced endothelial-to-mesenchymal transition in vitro; knockdown reversed these effects.
• In the mouse model, SOX18 overexpression aggravated endometriotic lesion development, confirming its pathogenic role.
• SOX18 directly bound the OTUB1 promoter, upregulating its expression, which led to YAP1 deubiquitination and stabilization, driving Hippo pathway activation.
• These findings suggest a molecular cascade (SOX18 → OTUB1 → YAP1) as a driver of lesion persistence and progression.

Strengths and Limitations:

• Combined molecular, cellular, and animal model evidence which provides mechanistic depth; and clear demonstration of transcriptional regulation that strengthens causality are the strengths of the study.
• Limitations include the reliance on Ishikawa cells instead of patient-derived primary endometrial cells; the absence of large clinically validated patient cohorts, and the lack of exploration of alternative SOX18-regulated pathways.

From the Editor-in-Chief – EndoNews

"This study elegantly dissects the molecular underpinnings of endometriosis by pinpointing the SOX18–OTUB1–YAP1 axis as a key pathogenic driver. The integration of patient tissues, cell-line experiments, and animal models provides compelling mechanistic evidence that transcriptional activation of OTUB1 by SOX18 leads to Hippo pathway dysregulation and stabilization of YAP1—a known promoter of cell proliferation and survival.

The novelty lies not only in confirming SOX18 overexpression in ectopic endometrium but also in establishing a direct regulatory link to OTUB1. Importantly, OTUB1 is already recognized as an ERα-interacting protein that deubiquitinates and stabilizes ERα, suggesting that this molecule may serve as a molecular bridge between classical estrogen signaling and Hippo/YAP1 pathway activity. This dual regulatory role positions OTUB1 as a particularly attractive therapeutic target.

Nevertheless, translation to clinical application requires caution. Reliance on Ishikawa cells highlights the need for validation in primary endometrial epithelial cells and across larger patient cohorts. Moreover, other signaling pathways potentially regulated by SOX18 (e.g., NF-κB, PI3K–Akt) remain unexplored.

Overall, this work reframes endometriosis as not only an inflammatory and hormonal disease but also one driven by transcriptional and post-translational regulatory networks. The therapeutic implication is compelling: interventions targeting SOX18 or its downstream OTUB1–YAP1 axis could disrupt multiple converging oncogenic-like pathways, opening new avenues for treatment."

Lay Summary

The transcription factor SOX18 (SRY-related high-mobility group box 18) has been identified as a key contributor to the pathogenesis of endometriosis, according to a new study published in the Journal of Translational Medicine by a team from The Second Affiliated Hospital of Nanchang University, China.

Endometriosis is already known to be associated with elevated SOX18 expression in ectopic compared with eutopic endometrial tissue. In this study, Dr. Jiayan Wu and colleagues investigated the expression pattern of SOX18 in women with endometriosis and explored its downstream effects on cellular function.

Using endometrial tissue samples and a combination of in vitro and in vivo models, the researchers demonstrated that SOX18 upregulation promotes the proliferation, migration, invasion, and endothelial-to-mesenchymal transition of Ishikawa cells (an endometrial adenocarcinoma-derived cell line). Conversely, SOX18 knockdown suppressed these malignant-like behaviors. In a mouse model, SOX18 overexpression accelerated the development and progression of endometriotic lesions. 

Mechanistically, SOX18 was shown to bind directly to the promoter region of OTUB1, enhancing its transcription. This, in turn, led to the deubiquitination and stabilization of YAP1, a central effector of the Hippo pathway. Rescue experiments confirmed that SOX18’s effects on YAP1 were mediated through OTUB1.

Collectively, these findings define a new SOX18–OTUB1–YAP1 signaling axis that drives the pathogenesis of endometriosis. The authors conclude that therapeutic strategies aimed at targeting this axis could represent a novel and promising approach for managing the disease.

Finally, the researchers demonstrated that SOX18 exerted its activity by directly binding to the promoter region of the OTUB1 gene and activating its expression. OTUB1 then deubiquitinated YAP1 and increased its stability. Through rescue experiments, the researchers demonstrated that SOX18 modulated the expression of YAP1 by upregulating OTUB1.

This, they said, demonstrated the role of the SOX18-OTUB1-YAP1 axis in endometriosis and suggests that targeting this axis “may be a promising treatment strategy” for endometriosis.

Research Source: https://pubmed.ncbi.nlm.nih.gov/40500704/