H2AFX modulates lung adenocarcinoma cell progression through the PPM1G-MAPK signaling axis

Objectives Lung cancer remains a leading cause of cancer-related deaths worldwide with high incidence and mortality rates, and conventional treatments provide limited overall survival benefits. H2AFX plays a critical role in maintaining chromatin integrity and genomic stability. However, H2AFX is significantly involved in the development and progression of multiple carcinomas. Surprisingly, H2AFX acts as a tumor suppressor gene in head and neck squamous cell carcinoma. The expression patterns of H2AFX in lung adenocarcinoma and its mechanistic role in tumorigenesis remain unclear. Methods Cell viability was assessed via the CCK-8 assay. Cell invasion and migration were evaluated using transwell and scratch wound healing assays, respectively. Apoptosis rates were quantified by flow cytometry with Annexin V-FITC and PI staining. Western blotting and polymerase chain reaction quantified H2AFX and PPM1G expression levels. High-throughput RNA-sequencing identified downstream signaling molecules. The interaction between H2AFX and PPM1G was detected through co-immunoprecipitation. Animal experiments revealed tumor growth dynamics. Overall survival of LUAD patients was analyzed via the Kaplan-Meier curve. Results H2AFX expression was markedly elevated in LUAD tissues relative to adjacent normal tissues, correlating strongly with poorer patient prognosis. Significantly, H2AFX knockdown substantially suppressed cell proliferation, invasion, and migration while promoting apoptosis in NCI-H358 cells. Conversely, H2AFX overexpression stimulated proliferation, invasion, and migration while inhibiting apoptosis in PC-9 cells. RNA-seq analysis revealed distinct differentially expressed gene profiles. Critically, co-immunoprecipitation assays confirmed a direct interaction between H2AFX and PPM1G. Subsequent PPM1G knockdown in H2AFX-overexpressing cells sharply increased p-MEK and p-MAPK expression levels. Furthermore, combined H2AFX knockdown and PPM1G overexpression demonstrably decreased p-MEK and p-MAPK levels in Western blot analyses. Collectively, our findings demonstrate that H2AFX drives malignant progression in lung adenocarcinoma cells primarily through the PPM1G-MAPK signaling pathway. Conclusions H2AFX drives proliferation, invasion, and migration in LUAD via the PPM1G-MAPK signaling pathway. Therefore, H2AFX holds significant promise as a therapeutic target for LUAD, offering a novel approach to combat lung cancer.