Identification of SETD4 as an Onco‐Immunological Biomarker Encompassing the Tumor Microenvironment, Prognoses, and Therapeutic Responses in Various Human Cancers
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 quiesc...
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| Format: | Article |
| Language: | English |
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Wiley
2025-01-01
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| Series: | Immunity, Inflammation and Disease |
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| Online Access: | https://doi.org/10.1002/iid3.70126 |
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| author | Yuyun Zhong Ruiqi Wang Zijie Huang Zhaoting Hu Bin Peng Bin Chen Liyue Sun |
| author_facet | Yuyun Zhong Ruiqi Wang Zijie Huang Zhaoting Hu Bin Peng Bin Chen Liyue Sun |
| author_sort | Yuyun Zhong |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c9e03bbb8187430ca937787651eb7c75 |
| institution | Kabale University |
| issn | 2050-4527 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Immunity, Inflammation and Disease |
| spelling | doaj-art-c9e03bbb8187430ca937787651eb7c752025-02-06T07:50:38ZengWileyImmunity, Inflammation and Disease2050-45272025-01-01131n/an/a10.1002/iid3.70126Identification of SETD4 as an Onco‐Immunological Biomarker Encompassing the Tumor Microenvironment, Prognoses, and Therapeutic Responses in Various Human CancersYuyun Zhong0Ruiqi Wang1Zijie Huang2Zhaoting Hu3Bin Peng4Bin Chen5Liyue Sun6Department of Health Management Center The Third Affiliated Hospital of Southern Medical University Guangzhou ChinaDepartment of Pharmacy, Zhuhai People's Hospital Zhuhai Hospital Affiliated With Jinan University Zhuhai ChinaDepartment of Plastic Surgery, The First Affiliated Hospital of Jinan University Jinan University Guangzhou Guangdong ChinaDepartment of Health Management Center The Third Affiliated Hospital of Southern Medical University Guangzhou ChinaDepartment of Thoracic Surgery The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen People's Hospital Shenzhen ChinaDepartment of Health Management Center The Third Affiliated Hospital of Southern Medical University Guangzhou ChinaSecond Department of Oncology Guangdong Second Provincial General Hospital Guangzhou ChinaABSTRACT 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.https://doi.org/10.1002/iid3.70126cancer stemnesspancancerprognosisSETD4tumor microenvironment |
| spellingShingle | Yuyun Zhong Ruiqi Wang Zijie Huang Zhaoting Hu Bin Peng Bin Chen Liyue Sun Identification of SETD4 as an Onco‐Immunological Biomarker Encompassing the Tumor Microenvironment, Prognoses, and Therapeutic Responses in Various Human Cancers Immunity, Inflammation and Disease cancer stemness pancancer prognosis SETD4 tumor microenvironment |
| title | Identification of SETD4 as an Onco‐Immunological Biomarker Encompassing the Tumor Microenvironment, Prognoses, and Therapeutic Responses in Various Human Cancers |
| title_full | Identification of SETD4 as an Onco‐Immunological Biomarker Encompassing the Tumor Microenvironment, Prognoses, and Therapeutic Responses in Various Human Cancers |
| title_fullStr | Identification of SETD4 as an Onco‐Immunological Biomarker Encompassing the Tumor Microenvironment, Prognoses, and Therapeutic Responses in Various Human Cancers |
| title_full_unstemmed | Identification of SETD4 as an Onco‐Immunological Biomarker Encompassing the Tumor Microenvironment, Prognoses, and Therapeutic Responses in Various Human Cancers |
| title_short | Identification of SETD4 as an Onco‐Immunological Biomarker Encompassing the Tumor Microenvironment, Prognoses, and Therapeutic Responses in Various Human Cancers |
| title_sort | identification of setd4 as an onco immunological biomarker encompassing the tumor microenvironment prognoses and therapeutic responses in various human cancers |
| topic | cancer stemness pancancer prognosis SETD4 tumor microenvironment |
| url | https://doi.org/10.1002/iid3.70126 |
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