PRDM1通过调节USP15介导的SELENBP1去泛素化,促进甲状腺癌的铁变态反应和免疫逃逸。

IF 5.4 2区 医学 Q1 Medicine Journal of Endocrinological Investigation Pub Date : 2024-12-01 Epub Date: 2024-07-16 DOI:10.1007/s40618-024-02385-4
J Ma, Z Li, J Xu, J Lai, J Zhao, L Ma, X Sun
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引用次数: 0

摘要

背景:去泛素化酶泛素特异性肽酶15(USP15)在多种癌症中上调,并通过增加多种癌基因的表达促进肿瘤进展。本项目旨在探索 USP15 在甲状腺癌(TC)进展中的作用和机制:方法:使用实时定量聚合酶链反应(RT-qPCR)检测硒结合蛋白1(SELENBP1)、USP15、CCL2/5、CXCL10/11、IL-4和TGF-β1 mRNA水平。SELENBP1、USP15、GPX4、IL-10、Arg-1、颗粒酶 B、TNF-α 和 PR 结构域锌指蛋白 1 (PRDM1) 蛋白水平通过 Western 印迹检测。使用专用试剂盒测定铁+水平、丙二醛(MDA)和脂质-ROS水平。CD11b+CD206+阳性细胞的比例是通过流式细胞术检测的。使用体内异种移植肿瘤模型检测了 SELENBP1 对 TC 细胞生长的作用。经过 GeneMANIA 预测后,USP15 和 SELENBP1 之间的相互作用通过共免疫沉淀(CoIP)试验得到了验证。JASPAR预测了PRDM1与USP15启动子之间的结合,并使用染色质免疫沉淀(ChIP)和双荧光素酶报告实验进行了验证:结果:SELENBP1在TC受试者和细胞系中增高,体外敲除SELENBP1可抑制TC细胞的增殖、迁移、侵袭、免疫逃逸和诱导铁变态反应,体内敲除SELENBP1可阻断肿瘤生长。在机制上,USP15与SELENBP1相互作用,通过去除泛素维持其稳定。同时,USP15的上调是由转录因子PRDM1诱导的:结论:PRDM1介导的USP15转录可能通过去泛素化SELENBP1促进TC细胞的恶性行为,为TC治疗提供了一个很有前景的治疗靶点。
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PRDM1 promotes the ferroptosis and immune escape of thyroid cancer by regulating USP15-mediated SELENBP1 deubiquitination.

Background: The deubiquitinating enzyme Ubiquitin-specific peptidase 15 (USP15) is upregulated in various cancers and promotes tumor progression by increasing the expression of several oncogenes. This project is designed to explore the role and mechanism of USP15 in thyroid cancer (TC) progression.

Methods: Selenium-binding protein 1 (SELENBP1), USP15, CCL2/5, CXCL10/11, IL-4, and TGF-β1 mRNA levels were detected using real-time quantitative polymerase chain reaction (RT-qPCR). SELENBP1, USP15, GPX4, IL-10, Arg-1, Granzyme B, TNF-α, and PR domain zinc finger protein 1 (PRDM1) protein levels were examined by western blot assay. Fe+ level, malondialdehyde (MDA), and lipid-ROS levels were determined using special kits. The proportion of CD11b+CD206+ positive cells was detected using a flow cytometry assay. The role of SELENBP1 on TC cell growth was examined using a xenograft tumor model in vivo. After GeneMANIA prediction, the interaction between USP15 and SELENBP1 was verified using Co-immunoprecipitation (CoIP) assay. The binding between PRDM1 and USP15 promoter was predicted by JASPAR and validated using Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays.

Results: SELENBP1 was increased in TC subjects and cell lines, and its knockdown repressed TC cell proliferation, migration, invasion, immune escape, and induced ferroptosis in vitro, as well as blocked tumor growth in vivo. In mechanism, USP15 interacted with SELENBP1 and maintained its stabilization by removing ubiquitin. Meanwhile, the upregulation of USP15 was induced by the transcription factor PRDM1.

Conclusion: USP15 transcriptionally mediated by PRDM1 might boost TC cell malignant behaviors through deubiquitinating SELENBP1, providing a promising therapeutic target for TC treatment.

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来源期刊
Journal of Endocrinological Investigation
Journal of Endocrinological Investigation ENDOCRINOLOGY & METABOLISM-
CiteScore
8.10
自引率
7.40%
发文量
242
期刊介绍: The Journal of Endocrinological Investigation is a well-established, e-only endocrine journal founded 36 years ago in 1978. It is the official journal of the Italian Society of Endocrinology (SIE), established in 1964. Other Italian societies in the endocrinology and metabolism field are affiliated to the journal: Italian Society of Andrology and Sexual Medicine, Italian Society of Obesity, Italian Society of Pediatric Endocrinology and Diabetology, Clinical Endocrinologists’ Association, Thyroid Association, Endocrine Surgical Units Association, Italian Society of Pharmacology.
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