Histone Variant H2A.Z2 Hyper-Transcription Induced by E2F1 Accelerates Lung Adenocarcinoma Progression via the...

Lung adenocarcinoma (LUAD) is among the most common cancers and a leading cause of cancer-related deaths. The histone variant H2A.Z has two isoforms (H2A.Z1 and H2A.Z2) encoded by distinct paralogs. Increasing numbers of evidence have demonstrated that H2A.Z1 and H2A.Z2 play a critical role in the pathogenesis of various cancers. Nevertheless, the precise biological functions and underlying mechanisms of H2A.Z in LUAD remain unclear.

The levels of H2A.Z expression in LUAD were evaluated using immunohistochemistry (IHC) and western blot assays. To investigate the biological role of H2A.Z2 in LUAD cells, both in vitro and in vivo experiments were conducted. To evaluate gene expression alterations and predict downstream pathways, transcriptome sequencing was performed. To validate that E2F transcription factor 1 (E2F1) regulates H2A.Z2 expression, dual luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays were used.

Herein, we demonstrated high expression pattern of H2A.Z in LUAD tissues and its correlation with adverse clinical outcomes. Functionally, we indicated that H2A.Z2 exerts an oncogenic function in driving LUAD cell proliferation and metastasis. Mechanistically, analysis based on transcriptome sequencing suggested the influence of H2A.Z2 on the JAK-STAT pathway. Rescue experiments revealed that H2A.Z2 promotes LUAD progression by modulating STAT5B. Furthermore, we identified E2F1 as an activator that binds to the H2A.Z2 promoter to drive its transcription, thereby providing a novel mechanism of H2A.Z2 dysregulation.

In conclusion, our findings revealed a novel E2F1/H2A.Z2/STAT5B axis accelerating LUAD malignance, suggesting its potential as a promising target for diagnostic and therapeutic interventions in LUAD.