TP53 mutation–associated and copy number–dependent KDM7A-DT expression affects DNA repair and promotes invasive breast cancer progression

Abstract

Background: Recent characterisation of stress-induced promoter-associated antisense lncRNAs (si-paancRNAs) suggests that these lncRNAs modulate transcription, cellular responses to oxidative, metabolic and genotoxic stress, and may be part of the pathways critical in cancer. KDM7A divergent transcribed (KDM7A-DT) is among the top overexpressed genes encoded by such lncRNAs. The mechanisms leading to aberrant KDM7A-DT transcription, transcript biogenesis, and downstream functions of KDM7A-DT isoforms in breast cancer (BC) types and subtypes have not been studied. Methods: Cell line models, biochemistry methods and microarrays experiments for overexpression and knockdown of KDM7A-DT were used. Next, integration of experimental models, bioinformatics, and massive BRCA patient metadata analyses were performed to investigate the mechanisms and functions of KDM7A-DT.Results: The stable KDM7A-DT overexpression in non-malignant cells upregulates p53, CDKN1A, and γH2AX signalling, resulting in a prolonged cell growth retardation phenotype and preferential depletion of epithelial-to-mesenchymal transition (EMT) pathway–associated tumour suppressor genes. Importantly, KDM7A-DT induction by acute oxidative stress of semi-transformed fibroblasts is p53-dependent. According to BC clinical metadata, KDM7A-DT is overexpressed in poor survival basal-like BC (BLBC) subtype. The KDM7A-DT overexpression is associated with the overexpression of the TP53-missense mutated gene and KDM7A-DT full-length copy number amplification. KDM7A-DT overexpression affects DNA repair via the non-homologous end-joining (NHEJ) pathway, inhibits tumor suppressors involved in EMT, induces pro-oncogenic metabolic changes, and correlates with histologic grades, aneuploidy, hypoxia, cancer-associated proteins, clinical and molecular markers.Conclusion: KDM7A-DT is the TP53 mutation–associated and copy number–dependent pro-oncogene si-paancRNAs that contributes to genome instability, initiation, progression, invasiveness, and BLBC outcomes.