Identification of SETD4 as an Onco-Immunological Biomarker Encompassing the Tumor Microenvironment, Prognoses, and Therapeutic Responses in Various Human Cancers

IF 3.1 4区医学 Q3 IMMUNOLOGY

Immunity, Inflammation and Disease Pub Date : 2025-01-16 DOI:10.1002/iid3.70126

Yuyun Zhong, Ruiqi Wang, Zijie Huang, Zhaoting Hu, Bin Peng, Bin Chen, Liyue Sun

{"title":"Identification of SETD4 as an Onco-Immunological Biomarker Encompassing the Tumor Microenvironment, Prognoses, and Therapeutic Responses in Various Human Cancers","authors":"Yuyun Zhong, Ruiqi Wang, Zijie Huang, Zhaoting Hu, Bin Peng, Bin Chen, Liyue Sun","doi":"10.1002/iid3.70126","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>SET domain-containing protein 4 (SETD4) is a histone methyltransferase that has been shown to modulate cell proliferation, differentiation, and inflammatory responses by regulating histone H4 trimethylation (H4K20me3). Previous reports have demonstrated its function in the quiescence of cancer stem cells as well as drug resistance in several cancers. A limited number of systematic studies have examined SETD4's role in the tumor microenvironment, pathogenesis, prognosis, and therapeutic response.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Utilizing The Cancer Genome Atlas database, and other publicly accessible platforms, we comprehensively analyzed SETD4 gene expression, methylation patterns, and prognostic significance. Furthermore, we investigated its association with cancer-related pathways, the immune microenvironment, immunotherapy markers, and drug resistance signatures of chemotherapy. Additionally, qRT-PCR was performed to validate SETD4 expression in clinical specimens.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>The expression of SETD4 was abnormal across a variety of cancer types and the expression of SETD4 in colorectal cancer tissues was verified in clinical specimens. The upregulation of SETD4 may be a prognostic risk factor predicting poor overall survival and progression-free survival. The analysis revealed that the mRNA level of SETD4 was modulated by promoter methylation, and patients with lower methylation levels showed shorter survival times. Pathway analysis showed that SETD4 influenced several key cell cycle pathways, including the G2M checkpoint, and mitotic spindle pathways. In addition, SETD4 negatively affects immune cell infiltration in most cancers, including B cells, CD8 T cells, and macrophages. The correlation between SETD4 and cancer stemness as well as homologous recombination deficiency varied across tumor types, suggesting that SETD4 may play a multifaceted role in tumor resistance. Notably, we identified several potential agents targeting SETD4.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>This study demonstrates that SETD4 is an immune-oncogenic molecule in multiple cancers, with the potential to be a diagnosis, prognosis, and targeted therapy marker.</p>\n </section>\n </div>","PeriodicalId":13289,"journal":{"name":"Immunity, Inflammation and Disease","volume":"13 1","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736640/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunity, Inflammation and Disease","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/iid3.70126","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"IMMUNOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

SET domain-containing protein 4 (SETD4) is a histone methyltransferase that has been shown to modulate cell proliferation, differentiation, and inflammatory responses by regulating histone H4 trimethylation (H4K20me3). Previous reports have demonstrated its function in the quiescence of cancer stem cells as well as drug resistance in several cancers. A limited number of systematic studies have examined SETD4's role in the tumor microenvironment, pathogenesis, prognosis, and therapeutic response.

Methods

Utilizing The Cancer Genome Atlas database, and other publicly accessible platforms, we comprehensively analyzed SETD4 gene expression, methylation patterns, and prognostic significance. Furthermore, we investigated its association with cancer-related pathways, the immune microenvironment, immunotherapy markers, and drug resistance signatures of chemotherapy. Additionally, qRT-PCR was performed to validate SETD4 expression in clinical specimens.

Results

The expression of SETD4 was abnormal across a variety of cancer types and the expression of SETD4 in colorectal cancer tissues was verified in clinical specimens. The upregulation of SETD4 may be a prognostic risk factor predicting poor overall survival and progression-free survival. The analysis revealed that the mRNA level of SETD4 was modulated by promoter methylation, and patients with lower methylation levels showed shorter survival times. Pathway analysis showed that SETD4 influenced several key cell cycle pathways, including the G2M checkpoint, and mitotic spindle pathways. In addition, SETD4 negatively affects immune cell infiltration in most cancers, including B cells, CD8 T cells, and macrophages. The correlation between SETD4 and cancer stemness as well as homologous recombination deficiency varied across tumor types, suggesting that SETD4 may play a multifaceted role in tumor resistance. Notably, we identified several potential agents targeting SETD4.

Conclusions

This study demonstrates that SETD4 is an immune-oncogenic molecule in multiple cancers, with the potential to be a diagnosis, prognosis, and targeted therapy marker.

Abstract Image

查看原文本刊更多论文

SETD4作为肿瘤免疫生物标志物的鉴定，包括各种人类癌症的肿瘤微环境、预后和治疗反应。

背景：SET结构域蛋白4 （SETD4）是一种组蛋白甲基转移酶，已被证明通过调节组蛋白H4三甲基化（H4K20me3）来调节细胞增殖、分化和炎症反应。以前的报道已经证明了它在癌症干细胞的静止以及几种癌症的耐药性中的作用。有限数量的系统研究已经检测了SETD4在肿瘤微环境、发病机制、预后和治疗反应中的作用。方法：利用Cancer Genome Atlas数据库和其他可公开访问的平台，综合分析SETD4基因表达、甲基化模式和预后意义。此外，我们还研究了它与癌症相关途径、免疫微环境、免疫治疗标志物和化疗耐药特征的关系。此外，采用qRT-PCR方法验证SETD4在临床标本中的表达。结果：SETD4在多种癌症类型中均有异常表达，并在临床标本中证实了SETD4在结直肠癌组织中的表达。SETD4的上调可能是预测总生存期和无进展生存期较差的预后危险因素。分析显示，SETD4 mRNA水平受启动子甲基化调节，甲基化水平较低的患者生存时间较短。通路分析表明，SETD4影响了几个关键的细胞周期通路，包括G2M检查点和有丝分裂纺锤体通路。此外，SETD4对大多数癌症的免疫细胞浸润有负性影响，包括B细胞、CD8 T细胞和巨噬细胞。SETD4与肿瘤干性以及同源重组缺陷的相关性在不同肿瘤类型中存在差异，表明SETD4可能在肿瘤耐药中发挥多方面的作用。值得注意的是，我们确定了几种针对SETD4的潜在药物。结论：本研究表明SETD4在多种癌症中是一种免疫致癌分子，具有作为诊断、预后和靶向治疗标志物的潜力。

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分钟内获得全文求助全文

来源期刊

Immunity, Inflammation and Disease Medicine-Immunology and Allergy

CiteScore

3.60

自引率

0.00%

发文量

146

审稿时长

8 weeks

期刊介绍： Immunity, Inflammation and Disease is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research across the broad field of immunology. Immunity, Inflammation and Disease gives rapid consideration to papers in all areas of clinical and basic research. The journal is indexed in Medline and the Science Citation Index Expanded (part of Web of Science), among others. It welcomes original work that enhances the understanding of immunology in areas including: • cellular and molecular immunology • clinical immunology • allergy • immunochemistry • immunogenetics • immune signalling • immune development • imaging • mathematical modelling • autoimmunity • transplantation immunology • cancer immunology