Involvement of Xeroderma Pigmentosum Complementation Group G (XPG) in epigenetic regulation of T-Helper (TH) cell differentiation during breast cancer

Abstract

TNFα and IFN-γ secreted by CD4+T-Helper (TH) cells have antitumor activity followed by polarisation of TH1 phenotype in response to IL-12 secreted by dendritic cells, inducing expression of XPG, Nucleotide-Excision Repair (NER) complex component, which is downregulated in breast cancer. Therefore, we investigated the involvement of XPG in TH-cell differentiation in breast cancer. XPG knock-out (KO) PBMC and TH1 polarised CD4+ TH-cells isolated from breast cancer and control subjects blood samples were used to observe mRNA expressions of associated genes, % enrichment of corresponding epigenetic markers, and m6A RNA methylation levels to study the molecular mechanisms involved. Assays to investigate Cytotoxic T Lymphocyte (CTL) activity after cross-checking extracellular secretion levels. Our XPGKO results indicated upregulation of TH2 and Treg, downregulation of TH1, and negligible change for TH17; reduced expression of genes associated with tumour suppression (TP53, BRCA1) and DNA repair (H2AFX, ATM) for breast cancer TH-cells. CTCF associated TH1 specific function, reduced %enrichment of XPG, CSA, and ERCC1, increased %enrichment of γH2A.X, and altered histone modifications (methylation, deacetylation) at the IFN-γ gene locus in XPGKO breast cancer TH1-cells. Increased m6A RNA methylation mediated by XPG leads to TH1 cell specificity, further inducing CTL activity by releasing extracellular IFG-γ, which activates CD8+ CTLs. This article explores the association of the vital NER protein, XPG with the epigenetic modifications behind TH1 cell differentiation, augmenting the expressions of TH1-network genes to evoke protective immunity in breast cancer.