Abstract
Downregulation of MHC class I expression on tumour cells, a common mechanism by which tumour cells can escape from specific immune responses, can be associated with coordinated silencing of antigen-presenting machinery genes. The expression of these genes can be restored by IFNγ. In this study we documented association of DNA demethylation of selected antigen-presenting machinery genes located in the MHC genomic locus (TAP-1, TAP-2, LMP-2, LMP-7) upon IFNγ treatment with MHC class I upregulation on tumour cells in several MHC class I-deficient murine tumour cell lines (TC-1/A9, TRAMP-C2, MK16 and MC15). Our data also documented higher methylation levels in these genes in TC-1/A9 cells, as compared to their parental MHC class I-positive TC-1 cells. IFNγ-mediated DNA demethylation was relatively fast in comparison with demethylation induced by DNA methyltransferase inhibitor 5-azacytidine, and associated with increased histone H3 acetylation in the promoter regions of APM genes. Comparative transcriptome analysis in distinct MHC class I-deficient cell lines upon their treatment with either IFNγ or epigenetic agents revealed that a set of genes, significantly enriched for the antigen presentation pathway, was regulated in the same manner. Our data demonstrate that IFNγ acts as an epigenetic modifier when upregulating the expression of antigen-presenting machinery genes.
Highlights
Epigenetic changes, such as aberrant DNA methylation, play important roles in carcinogenesis [1,2] and namely in the tumour cell escape from anti-tumour immune responses [3,4]
We have shown that chemotherapy of MHC class I-deficient tumours with 5-azacytidine (5AC) in mice increased the expression of the antigen-presenting machinery (APM) genes and associated MHC class I molecule cell surface expression and we have demonstrated 5AC additive effects against MHC class I-deficient tumours when combined with immunotherapy
The principal aims of our study were to determine whether IFNγ acts as an epigenetic modifier inducing DNA demethylation and whether the mechanisms by which IFNγ upregulates the expression of selected genes in MHC class I-deficient tumour cells and modifies their interactions with the immune system can be associated with DNA demethylation of the corresponding regulatory genes
Summary
Epigenetic changes, such as aberrant DNA methylation, play important roles in carcinogenesis [1,2] and namely in the tumour cell escape from anti-tumour immune responses [3,4]. The molecular defects responsible for impaired MHC class I expression on the tumour cell surface can be either irreversible (“hard”) or reversible (“soft”) [9]. The latter can be associated with coordinated silencing of antigen-presenting machinery (APM) genes in tumour cells [10,11] and the expression of these genes can www.impactjournals.com/oncotarget be restored by IFNγ [10,12]. Another study documented higher-order chromatin remodelling and subsequent histone hyperacetylation of the human MHC locus upon IFNγ-mediated activation of the JAK/STAT signalling pathway [14]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.