LncTRDMT1–5 promotes chromosomal instability through MSRB3-mediated cell cycle and DNA damage in breast cancer

Abstract

Objective Chromosomal instability (CIN) drives genomic structural variants (such as amplifications and deletions) and promotes tumor progression. Long noncoding RNAs are known to participate in key biological processes and CIN regulation. Our previous study demonstrated that the highly expressed lncTRDMT1–5 serves as a novel prognostic biomarker in breast cancer; however, its underlying mechanisms require further investigation. Methods LncTRDMT1–5 expression was knocked down in MDA-MB-231 cells, followed by chromosomal microarray analysis (CMA). Expression levels of lncTRDMT1–5 were examined in breast cancer cells and tissues via RT-PCR. Chromatin immunoprecipitation was used to detect H3K27 acetylation in the promoter region. RNA pull-down was performed to identified interactions with the MSRB3 protein. Cell proliferation was evaluated by EdU assay, DNA damage was assessed by γH2AX immunofluorescence, and cell cycle distribution was analyzed by flow cytometry. EMT-related protein expression and cell cycle regulators were examined by western blotting. Results LncTRDMT1–5 was significantly upregulated in breast cancer cells and tissues, with H3K27 acetylation detected in its promoter. Downregulation of lncTRDMT1–5 induced CNVs across different chromosomes. Overexpression of lncTRDMT1–5 promoted cell proliferation, DNA damage, and EMT-related protein expression. RNA pulldown confirmed the relationship between lncTRDMT1–5 and MSRB3 protein. Mechanistically, lncTRDMT1–5 regulated cell cycle arrest by inhibiting p53 and inducing the expression of cell-division cycle protein 20 homologue (CDC20). Conclusion Overexpression of lncTRDMT1–5 in breast cancer induces CIN and tumor progression by promoting EMT process and increasing MSRB3, p53 and CDC20 protein expression. Targeting this molecular pathway may offer novel therapeutic strategies and improve prognostic evaluations.