Clinical significance and molecular mechanism of CDX2-CBX3 regulatory axis in lung adenocarcinoma progression

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, with chemotherapy resistance and tumor heterogeneity posing significant challenges. The Chromobox (CBX) protein family, crucial epigenetic regulators in tumor progression, has not been systematically characterized in LUAD. This study aimed to develop a CBX-based molecular classification system for LUAD and explore the mechanistic role of the CDX2-CBX3 regulatory axis in tumor progression. Through multiomics analysis of TCGA-LUAD data, four distinct CBX subtypes were identified, each associated with variations in survival, clinical stage, DNA repair pathway activation, and immune cell infiltration. Mechanistic investigations (ChIP-qPCR, luciferase assays, and gain/loss-of-function experiments) confirmed that CDX2 directly upregulates CBX3 transcription via conserved promoter binding. CDX2 overexpression enhanced migration, invasion, and xenograft growth, whereas CBX3 knockdown suppressed these phenotypic changes. In conclusion, this study defines clinically relevant CBX molecular subtypes in LUAD and reveals the CDX2-CBX3 transcriptional cascade as a novel driver of tumor progression, offering potential targets for precision therapy.