DNA methylation and repressive H3K9 and H3K27 trimethylation in the promoter regions of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and PD-L1 genes in human primary breast cancer
| Autor: | Eyad Elkord, Anne John, Varun Sasidharan Nair, Rowaida Z. Taha, Bassam R. Ali, Haytham El Salhat |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Bisulfite sequencing Programmed Cell Death 1 Receptor lcsh:Medicine B7-H1 Antigen Epigenesis Genetic Histones 0302 clinical medicine Breast cancer Tumor Microenvironment CTLA-4 Antigen Receptors Immunologic Promoter Regions Genetic Hepatitis A Virus Cellular Receptor 2 Genetics (clinical) DNA methylation Manchester Cancer Research Centre biology Reverse Transcriptase Polymerase Chain Reaction Middle Aged Lymphocyte Activation Gene 3 Protein Gene Expression Regulation Neoplastic Histone CpG site 030220 oncology & carcinogenesis Female Adult PD-L1 lcsh:QH426-470 Breast Neoplasms 03 medical and health sciences TIGIT Antigens CD Genetics Humans Epigenetics Molecular Biology Aged ResearchInstitutes_Networks_Beacons/mcrc Research Gene Expression Profiling lcsh:R Immune checkpoint lcsh:Genetics 030104 developmental biology Histone trimethylation biology.protein Cancer research Immune checkpoints CpG Islands Chromatin immunoprecipitation Developmental Biology |
| Zdroj: | Clinical Epigenetics, Vol 10, Iss 1, Pp 1-12 (2018) Clinical Epigenetics Sasidharan Nair, V, El Salhat, H, Taha, R Z, John, A, Ali, B R & Elkord, E 2018, ' DNA methylation and repressive H3K9 and H3K27 trimethylation in the promoter regions of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and PD-L1 genes in human primary breast cancer ', Clinical Epigenetics, vol. 10, no. 1 . https://doi.org/10.1186/s13148-018-0512-1 |
| ISSN: | 1868-7083 1868-7075 |
| Popis: | Background High expression of immune checkpoints in tumor microenvironment plays significant roles in inhibiting anti-tumor immunity, which is associated with poor prognosis and cancer progression. Major epigenetic modifications in both DNA and histone could be involved in upregulation of immune checkpoints in cancer. Methods Expressions of different immune checkpoint genes and PD-L1 were assessed using qRT-PCR, and the underlying epigenetic modifications including CpG methylation and repressive histone abundance were determined using bisulfite sequencing, and histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 27 trimethylation (H3K27me3) chromatin immunoprecipitation assays (ChIP), respectively. Results We first assessed the expression level of six immune checkpoints/ligands and found that PD-1, CTLA-4, TIM-3, and LAG-3 were significantly upregulated in breast tumor tissues (TT), compared with breast normal tissues (NT). We investigated the epigenetic modifications beyond this upregulation in immune checkpoint genes. Interestingly, we found that CpG islands in the promoter regions of PD-1, CTLA-4, and TIM-3 were significantly hypomethylated in tumor compared with normal tissues. Additionally, CpG islands of PD-L1 promoter were completely demethylated (100%), LAG-3 were highly hypomethylated (80–90%), and TIGIT were poorly hypomethylated (20–30%), in both NT and TT. These demethylation findings are in accordance with the relative expression data that, out of all these genes, PD-L1 was highly expressed and completely demethylated and TIGIT was poorly expressed and hypermethylated in both NT and TT. Moreover, bindings of H3K9me3 and H3K27me3 were found to be reduced in the promoter loci of PD-1, CTLA-4, TIM-3, and LAG-3 in tumor tissues. Conclusion Our data demonstrate that both DNA and histone modifications are involved in upregulation of PD-1, CTLA-4, TIM-3, and LAG-3 in breast tumor tissue and these epigenetic modifications could be useful as diagnostic/prognostic biomarkers and/or therapeutic targets in breast cancer. Electronic supplementary material The online version of this article (10.1186/s13148-018-0512-1) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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