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

Author:

Giannakakis Antonis1,Tsifintaris Margaritis1,Triantafyllou Charisios1,Gouzouasis Vasileios1,Ow Ghim Siong2,Aau Mei Yee2,Papp Csaba3,Ivshina Anna V.2,Kuznetsov Vladimir A.3

Affiliation:

1. Democritus University of Thrace

2. Bioinformatics Institute

3. SUNY Upstate Medical University

Abstract

Abstract 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.

Publisher

Research Square Platform LLC

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