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    PD-L1 Expression in human breast cancer stem cells Is epigenetically regulated through posttranslational histone modifications

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    Authors
    Darvin, P
    Sasidharan, N
    Elkord, Eyad
    Affiliation
    Cancer Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
    Issue Date
    2019
    
    Metadata
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    Abstract
    Tumor progression through immune evasion is a major challenge in cancer therapy. Recent studies revealed that enhanced PD-L1 expression in cancer stem cells is linked to immune evasion. Understanding the mechanisms behind this PD-L1 overexpression in cancer stem cells is critical for developing more effective strategies for preventing immune evasion and increasing the efficacy of anti-PD-1/PD-L1 therapy. Tumorsphere formation in breast cancer cells enhanced epithelial to mesenchymal transition (EMT), which is evident by increased expression of mesenchymal markers. In this study, we analyzed CpG methylation of PD-L1 promoter in MCF-7 and BT-549 breast cancer cells and tumorspheres derived from them. PD-L1 promoter was significantly hypomethylated in MCF-7 tumorspheres, but not from BT-549 tumorspheres, compared with their cell line counterparts. The active demethylation of PD-L1 promoter was confirmed by the increase in the distribution of 5hmC and decrease in 5mC levels and the upregulation of TET3 and downregulation of DNMTs enzymes in MCF-7 tumorspheres, compared with the cell line. Additionally, we checked the distribution of repressive histones H3K9me3, H3K27me3, and active histone H3K4me3 in the PD-L1 promoter. We found that distribution of repressive histones to the PD-L1 promoter was lower in tumorspheres, compared with cell lines. Moreover, an overexpression of histone acetylation enzymes was observed in tumorspheres suggesting the active involvement of histone modifications in EMT-induced PD-L1 expression. In summary, EMT-associated overexpression of PD-L1 was partially independent of promoter CpG methylation and more likely to be dependent on posttranslational histone modifications.
    Citation
    Darvin P, Sasidharan Nair V, Elkord E. PD-L1 Expression in Human Breast Cancer Stem Cells Is Epigenetically Regulated through Posttranslational Histone Modifications. J Oncol. 2019;2019:3958908.
    Journal
    Journal of Oncology
    URI
    http://hdl.handle.net/10541/621746
    DOI
    10.1155/2019/3958908
    PubMed ID
    30915120
    Additional Links
    https://dx.doi.org/10.1155/2019/3958908
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1155/2019/3958908
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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