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
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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.

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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。
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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
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