The DLX1-NCS1-MYC axis drives oncogenesis and progression in lung adenocarcinoma

Lung adenocarcinoma (LUAD) remains the leading cause of cancer-related mortality globally, yet the transcriptional drivers of its progression are incompletely elucidated. Here, we identify DLX1, a novel homeobox transcription factor, as a pivotal oncogenic regulator in LUAD. Integrative transcriptomic analyses of RNA-sequencing and microarray datasets reveal significant overexpression of DLX1 in LUAD tissues compared to normal lung, a finding validated across independent datasets including The Cancer Genome Atlas (TCGA) and TIMER. Elevated DLX1 expression is associated with advanced clinical stages, TP53 mutations, and poor overall survival. Functional studies underscore the essential role of DLX1 in LUAD tumorigenesis. Silencing DLX1 impairs cell proliferation, invasion, and colony formation in vitro while significantly suppressing tumor growth in vivo. Mechanistically, transcriptomic profiling coupled with Gene Set Enrichment Analysis (GSEA) identifies DLX1 as a regulator of MYC-driven oncogenic pathways. Importantly, NCS1 is uncovered as a direct transcriptional target of DLX1. Chromatin immunoprecipitation (ChIP) and luciferase assays demonstrate that DLX1 binds two conserved motifs within the NCS1 promoter, driving its transcriptional activation. Functionally, NCS1 restores proliferative and invasive properties in DLX1-deficient LUAD cells, establishing its role as a mediator of DLX1-dependent oncogenicity. Furthermore, NCS1 itself acts as an upstream regulator of c-MYC and is significantly upregulated in LUAD, with its expression correlating with advanced stages, TP53 mutations, and unfavorable clinical outcomes. Collectively, our findings delineate the DLX1-NCS1-MYC axis as a critical transcriptional network underpinning LUAD progression.