USP7 depletion potentiates HIF2α degradation and inhibits clear cell renal cell carcinoma progression.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY Cell Death & Disease Pub Date : 2024-10-15 DOI:10.1038/s41419-024-07136-0
Rongfu Tu, Junpeng Ma, Yule Chen, Ye Kang, Doudou Ren, Zeqiong Cai, Ru Zhang, Yiwen Pan, Yijia Liu, Yanyan Da, Yao Xu, Yahuan Yu, Donghai Wang, Jingchao Wang, Yang Dong, Xinlan Lu, Chengsheng Zhang
{"title":"USP7 depletion potentiates HIF2α degradation and inhibits clear cell renal cell carcinoma progression.","authors":"Rongfu Tu, Junpeng Ma, Yule Chen, Ye Kang, Doudou Ren, Zeqiong Cai, Ru Zhang, Yiwen Pan, Yijia Liu, Yanyan Da, Yao Xu, Yahuan Yu, Donghai Wang, Jingchao Wang, Yang Dong, Xinlan Lu, Chengsheng Zhang","doi":"10.1038/s41419-024-07136-0","DOIUrl":null,"url":null,"abstract":"<p><p>Clear cell renal cell carcinoma (ccRCC) is characterized by Von Hippel Lindau (VHL) gene loss of function mutation, which leads to the accumulation of hypoxia-inducible factor 2α (HIF2α). HIF2α has been well-established as one of the major oncogenic drivers of ccRCC, however, its therapeutic targeting remains a challenge. Through an analysis of proteomic data from ccRCCs and adjacent non-tumor tissues, we herein revealed that Ubiquitin-Specific Peptidase 7 (USP7) was upregulated in tumor tissues, and its depletion by inhibitors or shRNAs caused significant suppression of tumor progression in vitro and in vivo. Mechanistically, USP7 expression is activated by the transcription factors FUBP1 and FUBP3, and it promotes tumor progression mainly by deubiquitinating and stabilizing HIF2α. Moreover, the combination of USP7 inhibitors and afatinib (an ERBB family inhibitor) coordinately induce cell death and tumor suppression. In mechanism, afatinib indirectly inhibits USP7 transcription and accelerates the degradation of HIF2α protein, and the combination of them caused a more profound suppression of HIF2α abundance. These findings reveal a FUBPs-USP7-HIF2α regulatory axis that underlies the progression of ccRCC and provides a rationale for therapeutic targeting of oncogenic HIF2α via combinational treatment of USP7 inhibitor and afatinib.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1000,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482519/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death & Disease","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s41419-024-07136-0","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Clear cell renal cell carcinoma (ccRCC) is characterized by Von Hippel Lindau (VHL) gene loss of function mutation, which leads to the accumulation of hypoxia-inducible factor 2α (HIF2α). HIF2α has been well-established as one of the major oncogenic drivers of ccRCC, however, its therapeutic targeting remains a challenge. Through an analysis of proteomic data from ccRCCs and adjacent non-tumor tissues, we herein revealed that Ubiquitin-Specific Peptidase 7 (USP7) was upregulated in tumor tissues, and its depletion by inhibitors or shRNAs caused significant suppression of tumor progression in vitro and in vivo. Mechanistically, USP7 expression is activated by the transcription factors FUBP1 and FUBP3, and it promotes tumor progression mainly by deubiquitinating and stabilizing HIF2α. Moreover, the combination of USP7 inhibitors and afatinib (an ERBB family inhibitor) coordinately induce cell death and tumor suppression. In mechanism, afatinib indirectly inhibits USP7 transcription and accelerates the degradation of HIF2α protein, and the combination of them caused a more profound suppression of HIF2α abundance. These findings reveal a FUBPs-USP7-HIF2α regulatory axis that underlies the progression of ccRCC and provides a rationale for therapeutic targeting of oncogenic HIF2α via combinational treatment of USP7 inhibitor and afatinib.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
USP7 消耗可促进 HIF2α 降解并抑制透明细胞肾细胞癌的进展。
透明细胞肾细胞癌(ccRCC)的特点是Von Hippel Lindau(VHL)基因功能缺失突变,从而导致缺氧诱导因子2α(HIF2α)的积累。HIF2α 已被证实是 ccRCC 的主要致癌因素之一,但其靶向治疗仍是一项挑战。通过分析ccRCC和邻近非肿瘤组织的蛋白质组数据,我们发现泛素特异性肽酶7(USP7)在肿瘤组织中上调,通过抑制剂或shRNAs去除泛素特异性肽酶7可显著抑制体外和体内的肿瘤进展。从机理上讲,USP7的表达是由转录因子FUBP1和FUBP3激活的,它主要通过去泛素化和稳定HIF2α来促进肿瘤的进展。此外,USP7抑制剂与阿法替尼(ERBB家族抑制剂)联合使用可协调诱导细胞死亡和抑制肿瘤。从机制上看,阿法替尼间接抑制了USP7的转录,加速了HIF2α蛋白的降解,二者联合使用能更有效地抑制HIF2α的丰度。这些发现揭示了FUBPs-USP7-HIF2α调控轴是ccRCC进展的基础,并为通过USP7抑制剂和阿法替尼联合治疗靶向致癌HIF2α提供了理论依据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
期刊最新文献
Author Correction: EGFR-ERK induced activation of GRHL1 promotes cell cycle progression by up-regulating cell cycle related genes in lung cancer. VCP enhances autophagy-related osteosarcoma progression by recruiting USP2 to inhibit ubiquitination and degradation of FASN. G9a/DNMT1 co-targeting inhibits non-small cell lung cancer growth and reprograms tumor cells to respond to cancer-drugs through SCARA5 and AOX1. Inhibition of mitochondrial OMA1 ameliorates osteosarcoma tumorigenesis. Ror2 signaling regulated by differential Wnt proteins determines pathological fate of muscle mesenchymal progenitors.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1