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

Abstract

Transcription factor 21 (TCF21) and estrogen receptor beta (ERβ, encoded by ESR2) are highly expressed in endometriotic stromal cells (ESCs) and contribute to the pathogenesis of endometriosis. However, the exploration of TCF21 and ERβ 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 ERβ 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 ERβ by FOXM1. Moreover, in an endometriosis mousemodel, overexpressing PES1 effectively reduced the growth of ectopic lesions and suppressed TCF21 and ERβ 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 ERβ and TCF21 expression through heterodimer formation with FOXM1. Moreover, targeting PES1 could serve as a treatment method for endometriosis.

Keywords

adenovirus / endometriosis / estrogen pathway / pescadillo

References

[1] A. W. Horne, S. A. Missmer, BMJ2022, 379, e070750.

[2] P. G. Signorile, R. Viceconte, A. Baldi, Front. Med.2022, 9, 879015.

[3] P. R. C França, A. C. P. Lontra, P. D. Fernandes, Molecules2022, 27, 4034.

[4] S. W. Guo, Hum. Reprod. Update2009, 15, 441.

[5] E. Chantalat, M. C. Valera, C. Vaysse, E. Noirrit, M. Rusidze, A. Weyl, K. Vergriete, E. Buscail, P. Lluel, C. Fontaine, J. F. Arnal, F. Lenfant, Int. J. Mol. Sci.2020, 21, 2815.

[6] Q. Xue, Z. Lin, Y. H. Cheng, C. C. Huang, E. Marsh, P. Yin, M. P. Milad, E. Confino, S. Reierstad, J. Innes, S. E. Bulun, Biol. Reprod.2007, 77, 681.

[7] a)S. J. Han, S. Y. Jung, S. P. Wu, S. M. Hawkins, M. J. Park, S. Kyo, J. Qin, J. P. Lydon, S. Y. Tsai, M. J. Tsai, F. J. DeMayo, B. W. O’Malley, Cell2015, 163, 960. b)S. J. Han, J. E. Lee, Y. J. Cho, M. J. Park, B. W. O’Malley, Endocrinology2019, 160, 2495.

[8] a)P. L. Wu, Y. Zhou, C. Zeng, X. Li, Z. T. Dong, Y. F. Zhou, S. E. Bulun, Q. Xue, Biochim. Biophys. Acta. Gene Regulat. Mech.2018, 1861, 706. b)J. Zhu, P. Wu, C. Zeng, Q. Xue, Biol. Reprod.2021, 105, 128.

[9] a)M. L. Allende, A. Amsterdam, T. Becker, K. Kawakami, N. Gaiano, N. Hopkins, Genes Dev.1996, 10, 3141. b)S. Gessert, D. Maurus, A. Rössner, M. Kühl, Dev. Biol.2007, 310, 99. A. Lerch-Gaggl, J. Haque, J. Li, G. Ning, P. Traktman, S. A. Duncan, J. Biol. Chem.2002, 277, 45347.

[10] E. M. Sikorski, T. Uo, R. S. Morrison, A. Agarwal, J. Biol. Chem.2006, 281, 24423.

[11] M. Kellner, M. Rohrmoser, I. Forné, K. Voss, K. Bürger, B. Muhl, A. Gruber-Eber, E. Kremmer, A. Imhof, D. Eick, Exp. Cell Res.2015, 334, 146.

[12] Y. Z. Li, C. Zhang, J. P. Pei, W. C. Zhang, C. D. Zhang, D. Q. Dai, J. Cancer2022, 13, 268.

[13] a)L. Cheng, J. Li, Y. Han, J. Lin, C. Niu, Z. Zhou, B. Yuan, K. Huang, J. Li, K. Jiang, H. Zhang, L. Ding, X. Xu, Q. Ye, J. Clin. Investig.2012, 122, 2857. b)J. Li, Q. Zhuang, X. Lan, G. Zeng, X. Jiang, Z. Huang, IUBMB Life2013, 65, 1017.

[14] S. Borhani, A. L. Gartel, Expert Opin. Therap. Targets2020, 24, 205.

[15] D. R. Littler, M. Alvarez-Fernández, A. Stein, R. G. Hibbert, T. Heidebrecht, P. Aloy, R. H. Medema, A. Perrakis, Nucleic Acids Res.2010, 38, 4527.

[16] G. Pinton, S. Zonca, A. G. Manente, M. Cavaletto, E. Borroni, A. Daga, P. V. Jithesh, D. Fennell, S. Nilsson, L. Moro, Oncotarget2016, 7, 14366.

[17] a)J. Zhang, Z. Xu, H. Dai, J. Zhao, T. Liu, G. Zhang, Gynecol. Obstetr. Investig.2019, 84, 485. b)P. Jin, X. Chen, G. Yu, Z. Li, Q. Zhang, J. V. Zhang, Anti-Cancer Agents Med. Chem.2019, 19, 323.

[18] I. P. Ryan, E. D. Schriock, R. N. Taylor, J. Clin. Endocrinol. Metab.1994, 78, 642.

[19] K. J. Livak, T. D. Schmittgen, Methods2001, 25, 402.

[20] J. N. Xu, C. Zeng, Y. Zhou, C. Peng, Y. F. Zhou, Q. Xue, J. Clin. Endocrinol. Metab.2014, 99, 2795.

[21] a)Z. Jiang, Y. Zhang, X. Chen, Y. Wang, P. Wu, C. Wu, D. Chen, J. Transl. Med.2020, 18, 209. b)M. Nakaguro, S. Kiyonari, S. Kishida, D. Cao, Y. Murakami-Tonami, H. Ichikawa, I. Takeuchi, S. Nakamura, K. Kadomatsu, Cancer Sci.2015, 106, 237. c)Y. He, J. Xiang, Y. Li, W. Huang, F. Gu, Y. Wang, R. Chen, Cancer Med.2023, 12, 12622.

[22] X. Li, W. Wang, J. Wang, A. Malovannaya, Y. Xi, W. Li, R. Guerra, D. H. Hawke, J. Qin, J. Chen, Mol. Syst. Biol.2015, 11, 775.

[23] a)X. Jin, R. Fang, P. Fan, L. Zeng, B. Zhang, X. Lu, T. Liu, J. Exp. Clin. Cancer Res. CR2019, 38, 463. b)N. Ma, R. Hua, Y. Yang, Z. C. Liu, J. Pan, B. Y. Yu, Y. F. Sun, D. Xie, Y. Wang, Z. G. Li, J. Biomed. Sci.2023, 30, 20. c)Z. Bian, M. Zhou, K. Cui, F. Yang, Y. Cao, S. Sun, B. Liu, L. Gong, J. Li, X. Wang, C. Li, S. Yao, Y. Yin, S. Huang, B. Fei, Z. Huang, J. Exp. Clin. Cancer Res. CR2021, 40, 360.

[24] Y. B. Qiu, L. Y. Liao, R. Jiang, M. Xu, L. W. Xu, G. G. Chen, Z. M. Liu, Sci. Rep.2019, 9, 1032.

[25] a)B. D. Yilmaz, S. E. Bulun, Hum. Reprod. Update2019, 25, 473. b)C. Zeng, P. L. Wu, Z. T. Dong, X. Li, Y. F. Zhou, Q. Xue, Reproduction2020, 160, 481.

[26] M. Rohrmoser, M. Hölzel, T. Grimm, A. Malamoussi, T. Harasim, M. Orban, I. Pfisterer, A. Gruber-Eber, E. Kremmer, D. Eick, Mol. Cell. Biol.2007, 27, 3682.

[27] L. Cheng, B. Yuan, S. Ying, C. Niu, H. Mai, X. Guan, X. Yang, Y. Teng, J. Lin, J. Huang, R. Jin, J. Wu, B. Liu, S. Chang, E. Wang, C. Zhang, N. Hou, X. Cheng, D. Xu, X. Yang, S. Gao, Q. Ye, Sci. Adv.2019, 5, eaav1090.

[28] Y. Sun, Q. Wang, M. Wang, F. Sun, P. Qiao, A. Jiang, C. Ren, Z. Yu, T. Yang, Cell. Mol. Life Sci. CMLS2022, 80, 13.

[29] D. Kalathil, S. John, A. S. Nair, Front. Oncol.2020, 10, 626836.

[30] D. Balli, Y. Zhang, J. Snyder, V. V. Kalinichenko, T. V. Kalin, Cancer Res.2011, 71, 40.

[31] M. A. Khan, J. Sengupta, L. C. Giudice, S. Mittal, S. Kumar, S. D. Gupta, R. Sharma, A. R. Najwa, D. Ghosh, J. Endometr.2011, 3, 8.

[32] D. Kopanja, V. Chand, E. O’Brien, N. K. Mukhopadhyay, M. P. Zappia, A. Islam, M. V. Frolov, B. J. Merrill, P. Raychaudhuri, Cancer Res.2022, 82, 2458.

[33] a)N. K. Mukhopadhyay, V. Chand, A. Pandey, D. Kopanja, J. R. Carr, Y. J. Chen, X. Liao, P. Raychaudhuri, Sci. Rep.2017, 7, 46017. b)I. Wierstra, J. Alves, Biol. Chem.2006, 387, 949.

[34] a)D. A. Sanders, C. S Ross-Innes, D. Beraldi, J. S. Carroll, S. Balasubramanian, Genome Biol.2013, 14, R6. b)P. A. Madureira, R. Varshochi, D. Constantinidou, R. E. Francis, R. C. Coombes, K. M. Yao, E. W. Lam, J. Biol. Chem.2006, 281, 25167.

RIGHTS & PERMISSIONS

2023 2023 The Authors. View published by Shanghai Fuji Technology Consulting Co., Ltd, authorized by Professional Community of Experimental Medicine, National Association of Health Industry and Enterprise Management (PCEM) and JohnWiley & Sons Australia, Ltd.