DLX6 Drives Lung Adenocarcinoma Progression via the p27 Kip1 /CDK2‐CCNE1 Signaling Pathway

Distal-less homeobox genes (DLX) comprise a family of cell-type-specific transcription factors crucial for the differentiation of various cell types. Despite reports of their dysregulated expression in cancer, the functional roles of DLX6 in carcinogenesis remain poorly understood. This study investigated the role and underlying mechanisms of DLX6 in Lung adenocarcinoma (LUAD). Analysis of data from The Cancer Genome Atlas (TCGA) and Tissue Microarray (TMA) demonstrated that elevated DLX6 expression was associated with poor prognosis in LUAD patients. Both in vitro and in vivo experiments confirmed that DLX6 promoted LUAD growth. Mechanistically, DLX6 transcriptionally inhibited cyclin-dependent kinase inhibitor 1B (CDKN1B), leading to activation of the p27^Kip1/CDK2-CyclinE signaling axis and promoting the G1-to-S phase transition in the cell cycle. Functional rescue experiments confirmed that CDKN1B knockdown attenuated DLX6-mediated tumor growth. Furthermore, DLX6 was identified as a novel downstream target of miR-145, a tumor-suppressive microRNA. MiR-145 directly bound to DLX6, reducing its mRNA and protein levels and effectively counteracting DLX6's oncogenic effects. Collectively, these findings uncovered a previously uncharacterized role of DLX6 in LUAD development and proposed the miR-145/DLX6/p27^Kip1/CDK2-CyclinE signal axis as a potential therapeutic target for LUAD management.