USP22 promotes the proliferation and Sorafenib resistance of hepatocellular carcinoma cells via its deubiquitinase activity

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-05-07 DOI:10.1002/ctm2.70324

Xiaochen Wang, Yijie Su, Bei Lan, Xuanyuan Li, Bodi Zhang, Liang Zhang, Yingmei Wang, Chunze Zhang, Chenghao Xuan

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Abstract

Background

Hepatocellular carcinoma remains one of the most lethal cancers, characterized by poor prognosis and low life expectancy. Unfortunately, there are very few molecular therapeutic options available for it. Sorafenib is a current standard first-line treatment for advanced hepatocellular carcinoma, however, drug resistance significantly limits its therapeutic efficacy.

Methods

Ubiquitin-specific protease 22 (USP22) expression level and its prognostic significance in hepatocellular carcinoma were analyzed using The Cancer Genome Atlas (TCGA) database. A series of cellular experiments related to cell proliferation and ferroptosis, and mouse tumor-bearing experiments were performed to investigate the role of USP22 in hepatocellular carcinoma cell growth and Sorafenib resistance. Flag affinity purification coupled with mass spectrometry, co-immunoprecipitation, and ubiquitination assays were conducted to identify direct substrates of USP22. Spike-in chromatin-immunoprecipitation (ChIP)-seq, RNA-seq, and ChIP assays were employed to explore the transcriptional substrates of USP22 as an H2BK120ub deubiquitinase.

Results

Analysis of TCGA database reveals that USP22 is highly expressed in hepatocellular carcinoma tissues, which is closely associated with poor patient prognosis. Our data further indicates that USP22 promotes the proliferation of hepatocellular carcinoma cells via deubiquitinating and stabilizing cyclin-dependent kinase 11B (CDK11B). Additionally, USP22 acts as a novel inducer of Sorafenib resistance and suppresses Sorafenib-triggered ferroptosis in hepatocellular carcinoma cells. It reduces the transcription of transferrin receptor (TFRC) by decreasing H2BK120ub occupancy at TFRC transcription start site (TSS) downstream region, thereby inhibiting ferroptosis upon Sorafenib treatment. Finally, animal experiments confirm the role of USP22 in promoting hepatocellular carcinoma cell growth and Sorafenib resistance in vivo. Taken together, this study demonstrates that USP22 promotes hepatocellular carcinoma growth and inhibits Sorafenib-induced ferroptosis by deubiquitinating non-histone substrate CDK11B and histone H2B, respectively.

Conclusions

Our findings suggest USP22 as a promising prognostic biomarker and therapeutic target for hepatocellular carcinoma patients, particularly those with Sorafenib resistance.

Key points

USP22 promotes the proliferation of hepatocellular carcinoma cells by deubiquitinating and stabilizing cyclin-dependent kinase CDK11B.
USP22 enhances Sorafenib resistance of hepatocellular carcinoma cells by inhibiting ferroptosis through the USP22/H2BK120ub/TFRC axis.

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USP22通过其去泛素酶活性促进肝癌细胞增殖和索拉非尼耐药

肝细胞癌仍然是最致命的癌症之一，其特点是预后差，预期寿命低。不幸的是，很少有分子治疗的选择。索拉非尼是目前晚期肝细胞癌的标准一线治疗药物，但耐药严重限制了其治疗效果。方法利用美国癌症基因组图谱（TCGA）数据库分析肝癌组织中泛素特异性蛋白酶22 （USP22）的表达水平及其预后意义。通过一系列与细胞增殖和铁凋亡相关的细胞实验和小鼠荷瘤实验，探讨USP22在肝癌细胞生长和索拉非尼耐药中的作用。采用标记亲和纯化、质谱、共免疫沉淀和泛素化等方法鉴定USP22的直接底物。采用刺入染色质免疫沉淀(ChIP)-seq， RNA-seq和ChIP检测USP22作为H2BK120ub去泛素酶的转录底物。结果TCGA数据库分析显示，USP22在肝细胞癌组织中高表达，与患者预后不良密切相关。我们的数据进一步表明，USP22通过去泛素化和稳定周期蛋白依赖性激酶11B （CDK11B）促进肝癌细胞的增殖。此外，USP22作为一种新的索拉非尼耐药诱导剂，抑制索拉非尼引发的肝癌细胞铁下垂。它通过减少H2BK120ub在TFRC转录起始位点（TSS）下游区域的占用来减少转铁蛋白受体（TFRC）的转录，从而抑制索拉非尼治疗后的铁凋亡。最后，动物实验证实了USP22在体内促进肝癌细胞生长和索拉非尼耐药的作用。综上所述，本研究表明USP22分别通过去泛素化非组蛋白底物CDK11B和组蛋白H2B来促进肝细胞癌的生长并抑制索拉非尼诱导的铁凋亡。我们的研究结果表明，USP22是一种有希望的预后生物标志物和肝细胞癌患者的治疗靶点，特别是那些索拉非尼耐药的患者。USP22通过去泛素化和稳定细胞周期蛋白依赖性激酶CDK11B促进肝癌细胞增殖。USP22通过USP22/H2BK120ub/TFRC轴抑制铁凋亡，增强肝癌细胞索拉非尼耐药性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.