UTX interacts with p53 to upregulate DUSP8 and restrain MAPK-driven malignant progression in lung adenocarcinoma

UTX (ubiquitously transcribed X chromosome tetratricopeptide repeat protein), a histone H3K27 demethylase, has been implicated in diverse cancer-related processes. However, its role and regulatory mechanisms in lung adenocarcinoma (LUAD) remain unclear. This study investigated the tumor-suppressive function of UTX and its underlying epigenetic and transcriptional mechanisms in LUAD. UTX expression and prognostic significance were assessed using The Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA), and Kaplan-Meier Plotter databases. LUAD cells with UTX overexpression or dual specificity phosphatase 8 (DUSP8)/p53 knockdown were established. Functional assays included MTT proliferation assays, Transwell assays, reactive oxygen species (ROS) detection. Transcriptome sequencing identified downstream targets of UTX. Luciferase reporter, chromatin immunoprecipitation (ChIP), and co-immunoprecipitation (Co-IP) assays were performed to investigate the regulatory mechanism of UTX. MAPK and PI3K/AKT signaling were evaluated by western blotting and immunohistochemistry, while xenograft models were used for in vivo validation. UTX expression was reduced in tumor tissues and significantly associated with poorer clinical outcomes and unfavorable pathological features. UTX overexpression suppressed LUAD cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), accompanied by inhibition of MAPK and PI3K/AKT signaling and an increase in intracellular ROS levels. Integrated transcriptomic analyses identified DUSP8 as a key downstream effector positively correlated with UTX. Mechanistically, UTX promoted DUSP8 transcription through p53-dependent H3K27me3 demethylation at the DUSP8 promoter. p53 facilitated the recruitment of UTX to the DUSP8 promoter, and disruption of the UTX-p53 interaction impaired DUSP8 transcriptional activation. DUSP8 knockdown in UTX-overexpressing cells reactivated the MAPK pathway, diminished ROS buildup, and largely negated the tumor-suppressive phenotype induced by UTX both in vitro and in vivo. UTX acts as a tumor suppressor in LUAD by epigenetically activating DUSP8 via p53-dependent H3K27me3 demethylation, thereby dampening MAPK-driven oncogenic signaling. These findings reveal a previously unrecognized UTX/p53-DUSP8 regulatory axis with potential therapeutic relevance for LUAD.