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
DOI: 10.1186/s13148-018-0512-1
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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