GJB2, a novel transcription target of HSF4, confers tumorigenic and metastatic phenotypes and sustains mitochondrial homeostasis in lung adenocarcinoma via the PI3K/AKT pathway.

The ion channel gene GJB2 emerges as a therapeutic target for LUAD with significant prognostic value. Herein, the potential mechanisms of GJB2 were investigated. GJB2 expression was analyzed by bioinformatics, RT-qPCR and western blotting. In vitro functional assays and A549 xenografts detected the role of GJB2. The upstream mechanism of GJB2 was explored. GJB2 was up-regulated and associated with the poor overall survival of LUAD patients. GJB2 knockdown inhibited cell malignancy and impaired mitochondrial homeostasis. HSF4 enhanced GJB2 transcription. GJB2 knockdown lowered PI3K/AKT activity. SC79 reversed the in vitro impacts of GJB2 inadequacy and promoted tumor growth when HSF4 was up-regulated and GJB2 was down-regulated simultaneously. GJB2, transcriptionally activated by HSF4, activates PI3K/AKT pathway to support LUAD tumorigenesis and development.