E2F1-induced H2A.Z2 hyper-transcription accelerates lung adenocarcinoma progression via JAK-STAT pathway

Lung adenocarcinoma (LUAD) is a prevalent and deadly cancer, necessitating a deeper understanding of its molecular drivers. Histone variant H2A.Z, with its isoforms H2A.Z1 and H2A.Z2, is increasingly recognized for its role in various cancers. However, the precise biological functions and underlying mechanisms of H2A.Z in LUAD pathogenesis have remained largely undefined, representing a critical knowledge gap this research aims to address.

Researchers evaluated H2A.Z expression in LUAD tissues using immunohistochemistry (IHC) and western blot assays. To elucidate the biological role of H2A.Z2 in LUAD cells, both in vitro and in vivo experiments were conducted. Gene expression alterations and downstream pathways were predicted via transcriptome sequencing. To confirm that E2F transcription factor 1 (E2F1) regulates H2A.Z2 expression, dual luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays were employed.

The study demonstrated a high expression pattern of H2A.Z in LUAD tissues, which correlated with adverse clinical outcomes. Functionally, H2A.Z2 was found to exert an oncogenic role, actively driving LUAD cell proliferation and metastasis. Mechanistically, transcriptome sequencing analysis strongly suggested that H2A.Z2 influences the JAK-STAT pathway. Rescue experiments further revealed that H2A.Z2 promotes LUAD progression specifically by modulating STAT5B activity.

Furthermore, E2F1 was identified as a key activator that directly binds to the H2A.Z2 promoter, thereby driving its transcription and providing a novel mechanism for H2A.Z2 dysregulation in LUAD.