Integrated bioinformatics profiling of the lysine demethylase gene family in breast cancer

Abstract Purpose Lysine demethylases (KDMs) are critical regulators of gene expression and chromatin remodeling, playing key roles in cancer development and progression. Given their involvement in epigenetic modifications, KDM family members have emerged as potential therapeutic targets in various malignancies. This study aimed to investigate the expression profiles, prognostic value, genetic alterations, and drug sensitivity associations of KDM genes across breast cancer (BC) using comprehensive bioinformatics analyses. Methods We utilized multiple online databases, including UALCAN, bc-GenExMiner, Kaplan-Meier Plotter, cBioPortal, STRING, Enrichr, MethSurv, GSCALite, and TIMER, to analyze mRNA expression patterns, clinicopathological correlations, survival outcomes (overall survival [OS] and relapse-free survival [RFS]), genetic alterations, protein-protein interaction (PPI) networks, Gene Ontology (GO) and KEGG pathways, CpG methylation, drug sensitivity, and immune infiltration in BC and pan-cancer contexts. Results KDM genes exhibited distinct expression patterns across BC subtypes, with significant associations with OS (e.g., KDM5B, HR = 1.5, p < 0.05) and RFS. Genetic alterations, primarily amplifications, were frequent, with KDM5B showing the highest rate (18%). PPI analysis identified KDM6A, KDM6B, and KDM1A as key hubs. GO and KEGG analyses linked KDMs to histone demethylation, chromatin remodeling, and metabolic pathways. CpG methylation analysis revealed prognostic relevance, with 35 CpG sites in KDM2B significantly associated with survival ( p < 0.05). Drug sensitivity analysis showed negative correlations between KDM expression (e.g., KDM2B, r =-0.51, FDR = 1.11E-49) and chemotherapy response (e.g., Methotrexate, Doxorubicin). TIMER analysis highlighted KDMs’ immunomodulatory roles, particularly in CD8 + T cells (KDM5A, r = 0.387, p = 3.43e-36), macrophages, and dendritic cells. Conclusions Our findings provide novel insights into the multifaceted roles of KDM genes in BC, emphasizing their potential as prognostic biomarkers and therapeutic targets.