Xiaochen Wang, Yijie Su, Bei Lan, Xuanyuan Li, Bodi Zhang, Liang Zhang, Yingmei Wang, Chunze Zhang, Chenghao Xuan
{"title":"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","authors":"Xiaochen Wang, Yijie Su, Bei Lan, Xuanyuan Li, Bodi Zhang, Liang Zhang, Yingmei Wang, Chunze Zhang, Chenghao Xuan","doi":"10.1002/ctm2.70324","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>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 <i>TFRC</i> 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.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>Our findings suggest USP22 as a promising prognostic biomarker and therapeutic target for hepatocellular carcinoma patients, particularly those with Sorafenib resistance.</p>\n </section>\n \n <section>\n \n <h3> Key points</h3>\n \n <div>\n <ul>\n \n <li>\n <p>USP22 promotes the proliferation of hepatocellular carcinoma cells by deubiquitinating and stabilizing cyclin-dependent kinase CDK11B.</p>\n </li>\n \n <li>\n <p>USP22 enhances Sorafenib resistance of hepatocellular carcinoma cells by inhibiting ferroptosis through the USP22/H2BK120ub/TFRC axis.</p>\n </li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9000,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70324","citationCount":"0","resultStr":"{\"title\":\"USP22 promotes the proliferation and Sorafenib resistance of hepatocellular carcinoma cells via its deubiquitinase activity\",\"authors\":\"Xiaochen Wang, Yijie Su, Bei Lan, Xuanyuan Li, Bodi Zhang, Liang Zhang, Yingmei Wang, Chunze Zhang, Chenghao Xuan\",\"doi\":\"10.1002/ctm2.70324\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>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 <i>TFRC</i> 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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>Our findings suggest USP22 as a promising prognostic biomarker and therapeutic target for hepatocellular carcinoma patients, particularly those with Sorafenib resistance.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Key points</h3>\\n \\n <div>\\n <ul>\\n \\n <li>\\n <p>USP22 promotes the proliferation of hepatocellular carcinoma cells by deubiquitinating and stabilizing cyclin-dependent kinase CDK11B.</p>\\n </li>\\n \\n <li>\\n <p>USP22 enhances Sorafenib resistance of hepatocellular carcinoma cells by inhibiting ferroptosis through the USP22/H2BK120ub/TFRC axis.</p>\\n </li>\\n </ul>\\n </div>\\n </section>\\n </div>\",\"PeriodicalId\":10189,\"journal\":{\"name\":\"Clinical and Translational Medicine\",\"volume\":\"15 5\",\"pages\":\"\"},\"PeriodicalIF\":7.9000,\"publicationDate\":\"2025-05-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70324\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical and Translational Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/ctm2.70324\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical and Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ctm2.70324","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
USP22 promotes the proliferation and Sorafenib resistance of hepatocellular carcinoma cells via its deubiquitinase activity
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.
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.
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