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Prohibitin2/PHB2, Transcriptionally Regulated by GABPA, Inhibits Cell Growth via PRKN/Parkin-dependent Mitophagy in Endometriosis

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Abstract

Endometriosis (EMS) is a common benign gynecological disease affecting women of reproductive age. It is characterized by abnormal growth of endometrial tissue outside the uterine cavity, resulting in chronic pelvic pain and infertility. Endometrial physiological and pathological processes are intimately connected to autophagy. Mitophagy is an essential selective mode that protects cells from metabolic stress and hypoxia. Mitochondrial autophagy mediated by prohibitin 2 (PHB2) is dependent on the PRKN/Parkin pathway and is involved in numerous human diseases. Uncertainty remains as to whether mitophagy regulation by PHB2 contributes to the occurrence and progression of EMS. This study aims to investigate the mechanism underlying the role of PHB2 in EMS. This study detected the protein and mRNA expression of PHB2 in ectopic and normal endometrial tissues of ovarian EMS, in addition to ectopic endometrial cell line 12Z and endometrial stromal cell line KC02-44D for gene overexpression or knockdown. Cell function experiments and mitochondrial function experiments were conducted to investigate the role of PHB2 in the endometrium. Bioinformatic analysis and experiments were also used to investigate the upstream transcription factors that influence PHB2 expression. PHB2 was downregulated in ectopic endometrium, and PHB2 overexpression inhibited cell proliferation, migration, and invasion and promoted apoptosis. The upregulation of mitophagy markers, including Parkin and LC3II/I, and the downregulation of autophagy degradation markers P62 and TOMM20 in EMS suggest that PHB2 may contribute to cell proliferation, migration, invasion, and apoptosis via PRKN/Parkin-mediated mitophagy. Analysis and validation of bioinformatics data revealed that the transcription factor GABPA binds directly to the PHB2 promoter region and controls the transcriptional expression of PHB2. This study investigated the role of PHB2 in the onset of EMS. It inhibits EMS growth via PRKN/Parkin-mediated mitophagy, and GABPA controls the transcriptional disorder of PHB2. This study’s findings suggest a novel method for investigating the clinical potential of PHB2 in EMS.

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Funding

This study was supported by funding from the National Key Research and Development Program of China (No. 2017YFC1001204).

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Authors and Affiliations

  1. Department of Gynecology and Obstetrics, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China

    Yupeng Deng, Tong Lou & Chongdong Liu

  2. Beijing Rehabilitation Hospital, Capital Medical University, Beijing, 100144, China

    Lili Kong

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  1. Yupeng Deng
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Deng, Y., Lou, T., Kong, L. et al. Prohibitin2/PHB2, Transcriptionally Regulated by GABPA, Inhibits Cell Growth via PRKN/Parkin-dependent Mitophagy in Endometriosis. Reprod. Sci. 30, 3629–3640 (2023). https://doi.org/10.1007/s43032-023-01316-7

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