Upregulation of PRSS27 driven by super-enhancers attenuates oxidative stress and apoptosis via activating PI3K/AKT pathway in lung adenocarcinoma

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide. This study aims to elucidate the mechanisms by which super-enhancers (SEs) drive persistent oncogenic expression of protease serine 27 (PRSS27)—a previously uncharacterised gene in LUAD. Integrated multi-omics analyses, including histone H3 lysine 27 acetylation (H3K27ac) Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq), RNA sequencing (RNA-seq), and public datasets, identified PRSS27 as a LUAD-specific SE-regulated gene, with high expression correlating with poor prognosis. Functional assays demonstrated that inhibition of SEs (JQ-1 and i-BET151) suppressed LUAD cell viability, proliferation, and colony formation while promoting apoptosis. PRSS27 overexpression enhanced LUAD tumour growth in vitro and in vivo, decreased oxidative stress and apoptosis, and activated the PI3K/AKT signalling pathway. Mechanistically, CRISPR interference (CRISPRi), luciferase reporter assays, and chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) confirmed that the SE region at chr16:2689953-2714630 transcriptionally activated PRSS27. Notably, rescue assays showed that PRSS27 overexpression effectively mitigated inhibitor-induced oxidative stress and apoptosis of SEs. Collectively, these findings identify SE-driven activation of PRSS27 as a novel oncogene that promotes LUAD progression by modulating PI3K/AKT signalling pathway, highlighting its potential as a therapeutic target.