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Background Recent characterization of stress-induced promoter-associated antisense lncRNAs (si-paancRNAs) suggests that they modulate transcription and cellular responses to oxidative, metabolic and genotoxic stress and may participate in critical cancer pathways. KDM7A divergent transcript (KDM7A-DT) is one of such stress-induced lncRNAs, whose expression is found deregulated in breast cancer (BC). The mechanisms leading to aberrant KDM7A-DT transcription, biogenesis, and downstream functions in BC types and subtypes have not been studied. Methods Cell lines, biochemical methods, and profiling experiments were used for KDM7A-DT overexpression and knockdown. Integration of experimental models, bioinformatics, and massive BRCA patient metadata analyses were performed to investigate the mechanisms and functions of KDM7A-DT. Results Stable KDM7A-DT overexpression in nonmalignant cells upregulates p53, CDKN1A, and γH2AX signaling, resulting in a prolonged cell growth retardation phenotype. Importantly, KDM7A-DT induction by acute oxidative stress in semi-transformed fibroblasts is p53-dependent. According to BC clinical metadata, KDM7A-DT gene alterations are preferentially associated with TP53 missense mutations and highly aggressive, invasive, basal-like (BL) subtype BC poor outcomes. Overall, KDM7A-DT affects DNA repair via the nonhomologous end-joining pathway, inhibits tumor suppressors involved in epithelial-to-mesenchymal transition, induces oncogenic metabolic changes and G2/M checkpoint arrest, and correlates with histology, aneuploidy, hypoxia and BC-associated proteins. Conclusion KDM7A-DT is a TP53 mutation–associated and copy number–dependent pro-oncogene si-paancRNA that contributes to genome instability and modulates BC initiation, progression, invasiveness and outcomes.

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.