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AP-1 Subunit JUNB Promotes Invasive Phenotypes in Endometriosis

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Abstract

Endometriosis is a disease defined by the presence of abnormal endometrium at ectopic sites, causing pain and infertility in 10% of women. Mutations in the chromatin remodeling protein ARID1A (AT-rich interactive domain-containing protein 1A) have been identified in endometriosis, particularly in the more severe deep infiltrating endometriosis and ovarian endometrioma subtypes. ARID1A has been shown to regulate chromatin at binding sites of the Activator Protein 1 (AP-1) transcription factor, and AP-1 expression has been shown in multiple endometriosis models. Here, we describe a role for AP-1 subunit JUNB in promoting invasive phenotypes in endometriosis. Through a series of knockdown experiments in the 12Z endometriosis cell line, we show that JUNB expression in endometriosis promotes the expression of epithelial-to-mesenchymal transition genes co-regulated by ARID1A including transcription factors SNAI1 and SNAI2, cell adhesion molecules ICAM1 and VCAM1, and extracellular matrix remodelers LOX and LOXL2. In highly invasive ARID1A-deficient endometriotic cells, co-knockdown of JUNB is sufficient to suppress invasion. These results suggest that AP-1 plays an important role in the progression of invasive endometriosis, and that therapeutic inhibition of AP-1 could prevent the occurrence of deep infiltrating endometriosis.

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Data Availability

The previously published RNA-seq dataset analyzed herein is available at GEO: GSE121198. All other data generated or analyzed during this study are included in this published article.

Code Availability

Not applicable.

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Acknowledgements

We thank Drs. Jose Teixeira, John Risinger, Jeff MacKeigan, Peter Laird, Jamie Bernard, Victoria Bae-Jump, and Asgi Fazleabas for helpful discussions. M.R.W. was supported by an American Cancer Society Postdoctoral Fellowship (PF-17-163-02-DDC) and a National Cancer Institute Pathway to Independence Award (K99 CA252152). R.L.C was supported by a grant from the National Institute for Child Health and Human Development (R21 HD099383).

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  1. Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA

    Mike R. Wilson, Jake J. Reske & Ronald L. Chandler

  2. Department of Epigenetics, Van Andel Research Institute, Grand Rapids, MI, 49503, USA

    Ronald L. Chandler

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Contributions

Conceptualization: M.R.W. and R.L.C. Investigation: M.R.W. Methodology: M.R.W., J.J.R., and R.L.C. Resources: R.L.C. Formal analysis: M.R.W. and J.J.R. Data curation: M.R.W. and J.J.R. Writing—original draft: M.R.W. Writing—review and editing: M.R.W., J.J.R., and R.L.C. Funding acquisition: M.R.W. and R.L.C. Supervision: R.L.C. All authors read and approved the final manuscript.

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Correspondence to Ronald L. Chandler.

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Wilson, M.R., Reske, J.J. & Chandler, R.L. AP-1 Subunit JUNB Promotes Invasive Phenotypes in Endometriosis. Reprod. Sci. 29, 3266–3277 (2022). https://doi.org/10.1007/s43032-022-00974-3

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