Faculty Collaboration Database

The DLX1-NCS1-MYC axis drives oncogenesis and progression in lung adenocarcinoma. Biochim Biophys Acta Mol Basis Dis 2025 Oct;1871(7):167967

Date

07/05/2025

Pubmed ID

40614386

DOI

10.1016/j.bbadis.2025.167967

Scopus ID

2-s2.0-105009498782 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

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.

Author List

Zhang B, Huang H, Zou X, Li X, He J, Xu N, Liu B, Shen X, Liu W

Author

Wei Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Carcinogenesis
Cell Line, Tumor
Cell Proliferation
Disease Progression
Female
Gene Expression Regulation, Neoplastic
Homeodomain Proteins
Humans
Lung Neoplasms
Mice
Proto-Oncogene Proteins c-myc
Transcription Factors