HOXD11 promotes lung adenocarcinoma progression by transcriptionally activating CREB5 and enhancing AKT/mTOR signaling

Abstract Background Lung adenocarcinoma (LUAD) is one of the most prevalent and lethal forms of lung cancer globally. Understanding the molecular drivers of LUAD progression is critical for developing targeted therapies. Although HOX family transcription factors are known contributors to oncogenesis, the role of HOXD11 in LUAD remains unexplored. Methods Comprehensive in vitro and in vivo assays were employed to evaluate the function of HOXD11 in LUAD. Transcriptomic profiling (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and bioinformatic analyses were used to identify downstream targets. The impact of HOXD11 and its downstream effector CREB5 on LUAD cell growth, migration, and invasion was assessed through RNA interference, overexpression strategies, EdU incorporation, colony formation, Transwell, and scratch assays. Xenograft models in nude mice were used to validate tumorigenic potential. Protein and transcript levels were analyzed by Western blot and qRT-PCR, and immunohistochemistry was performed on tumor sections. Results HOXD11 expression was markedly elevated in LUAD tissues and cell lines and correlated with poor prognosis. Functional assays demonstrated that HOXD11 enhances LUAD cell proliferation, migration, and invasion in vitro and accelerates tumor growth in vivo. Mechanistic studies identified CREB5as a direct transcriptional target of HOXD11, as confirmed by ChIP-seq and luciferase reporter assays. CREB5 knockdown significantly abrogated the oncogenic effects of HOXD11. Moreover, the HOXD11-CREB5 axis was found to directly activate the AKT/mTOR signaling pathway, contributing to aggressive tumor behavior. Conclusion Our findings uncover a novel regulatory axis, HOXD11/CREB5/AKT/mTOR, that promotes LUAD progression both in vitro and in vivo. Targeting this pathway may represent a promising therapeutic strategy for patients with HOXD11-overexpressing LUAD.