Nuclear envelope proteins in cancer: revisiting the significance of LEM-domain proteins

Nuclear envelope dysfunction is increasingly recognized as a driver of cancer-associated alterations in chromatin organization, genome stability, and mechanotransduction. Among inner nuclear membrane components are the LEM-domain (LEM-D) proteins LAP2/TMPO, emerin (EMD), LEMD1, LEMD2, MAN1/LEMD3, ANKLE1, and ANKLE2. Accumulating evidence links dysregulation of these proteins to hallmark cancer processes, including cell-cycle control, epithelial-mesenchymal transition, genome instability, and therapeutic resistance. This review synthesizes recent mechanistic and translational findings on LEM-D proteins in cancer, highlighting isoform-specific functions, context-dependent oncogenic versus tumor-suppressive roles, and convergence on key pathways such as Wnt/β-catenin, PI3K/AKT, MAPK, and TGF-β signaling. Concrete evidence for prognostic value varies across the LEM-D proteins. While much of the current evidence derives from transcript-level and preclinical studies, emerging data suggest that LEM-D proteins contribute to nuclear stress adaptation and may represent context-dependent therapeutic vulnerabilities. We discuss their prognostic and predictive potential, critically evaluate limitations in current datasets, and present a unifying framework linking LEM-D dysfunction to genome instability, altered signalling, and therapy resistance. Thus, despite growing evidence of therapeutic potential, these proteins are better positioned as biomarkers to guide current therapies.