在人类子宫肌瘤细胞中靶向含溴结构域蛋白 9。

IF 2.6 3区 医学 Q2 OBSTETRICS & GYNECOLOGY
Reproductive Sciences Pub Date : 2025-01-01 Epub Date: 2024-06-10 DOI:10.1007/s43032-024-01608-6
Qiwei Yang, Ali Falahati, Azad Khosh, Somayeh Vafaei, Ayman Al-Hendy
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引用次数: 0

摘要

含溴结构域(Bromodomain,BRD)的蛋白质是一种进化保守的蛋白质-蛋白质相互作用模块,参与了许多生物过程。BRD 可选择性地识别并结合乙酰化赖氨酸残基,尤其是组蛋白中的乙酰化赖氨酸残基,从而在基因表达调控中发挥关键作用。BRD蛋白功能障碍与包括肿瘤发生在内的多种疾病有关。此前,我们报道了含 BRD 蛋白 9(BRD9)在 UFs 发病机制中的关键作用。本研究旨在扩展我们之前的发现,并进一步了解 BRD9 在 UFs 中的作用。我们的研究表明,使用强效抑制剂TP-472对BRD9进行靶向抑制,可通过增加UF细胞的凋亡和增殖抑制以及减少细胞外基质沉积来抑制UF的发病机制。高通量转录组分析进一步广泛证明,TP-472对BRD9的靶向抑制影响了细胞周期进展、炎症反应、E2F靶点、ECM沉积和m6A重编程等生物学通路。与之前的研究相比,我们发现了I-BRD9和TP-472这两种BRD9抑制剂诱导的共同富集通路。综上所述,我们的研究进一步揭示了BRD9在UF细胞中的关键作用。我们揭示了BRD9与其他重要通路之间的联系,以及参与尿毒症进展的表观遗传和表观转录组之间的联系。对 BRD 蛋白的靶向抑制可能会为这种育龄妇女最常见的良性肿瘤提供一种非激素治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Targeting Bromodomain-Containing Protein 9 in Human Uterine Fibroid Cells.

Targeting Bromodomain-Containing Protein 9 in Human Uterine Fibroid Cells.

Bromodomain (BRD)-containing proteins are evolutionarily conserved protein-protein interaction modules involved in many biological processes. BRDs selectively recognize and bind to acetylated lysine residues, particularly in histones, and thereby have a crucial role in the regulation of gene expression. BRD protein dysfunction has been linked to many diseases, including tumorigenesis. Previously, we reported the critical role of BRD-containing protein 9 (BRD9) in the pathogenesis of UFs. The present study aimed to extend our previous finding and further understand the role of the BRD9 in UFs. Our studies demonstrated that targeted inhibition of BRD9 with its potent inhibitor TP-472 inhibited the pathogenesis of UF through increased apoptosis and proliferation arrest and decreased extracellular matrix deposition in UF cells. High-throughput transcriptomic analysis further and extensively demonstrated that targeted inhibition of BRD9 by TP-472 impacted the biological pathways, including cell cycle progression, inflammatory response, E2F targets, ECM deposition, and m6A reprogramming. Compared with the previous study, we identified common enriched pathways induced by two BRD9 inhibitors, I-BRD9 and TP-472. Taken together, our studies further revealed the critical role of BRD9 in UF cells. We characterized the link between BRD9 and other vital pathways, as well as the connection between epigenetic and epitranscriptome involved in UF progression. Targeted inhibition of BRD proteins might provide a non-hormonal treatment strategy for this most common benign tumor in women of reproductive age.

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来源期刊
Reproductive Sciences
Reproductive Sciences 医学-妇产科学
CiteScore
5.50
自引率
3.40%
发文量
322
审稿时长
4-8 weeks
期刊介绍: Reproductive Sciences (RS) is a peer-reviewed, monthly journal publishing original research and reviews in obstetrics and gynecology. RS is multi-disciplinary and includes research in basic reproductive biology and medicine, maternal-fetal medicine, obstetrics, gynecology, reproductive endocrinology, urogynecology, fertility/infertility, embryology, gynecologic/reproductive oncology, developmental biology, stem cell research, molecular/cellular biology and other related fields.
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