Effect of EZH2 regulation of the JAK2/STAT3 signaling pathway on proliferation and apoptosis in non-small cell lung cancer cells

Abstract

Enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in non-small cell lung cancer (NSCLC) and is associated with aggressive tumor behavior and poor patient prognosis. However, the molecular mechanisms through which EZH2 drives NSCLC progression, particularly its interplay with major oncogenic signaling cascades, remain incompletely defined. EZH2 expression was analyzed using publicly available databases. Functional perturbations were achieved via short hairpin RNA (shRNA)-mediated knockdown in NCI-H1299 and A549 NSCLC cell lines. Cell proliferation, migration, invasion, apoptosis, and colony formation were assessed using Cell Counting Kit-8, Transwell, flow cytometry and colony formation assays, respectively. Involvement of the JAK2/STAT3 pathway was examined by western blotting and rescue experiments using a JAK2 agonist. In vivo validation was conducted using a xenograft mouse model. EZH2 was markedly upregulated in NSCLC tissues. Its silencing markedly suppressed cell proliferation, impaired migratory and invasive capacities, induced apoptosis, and curtailed tumor growth in vivo. Mechanistically, EZH2 silencing attenuated the phosphorylation of both JAK2 and STAT3. Crucially, the anti-tumor effects of EZH2 knockdown were effectively reversed by JAK2 agonism, positioning EZH2 upstream of the JAK2/STAT3 axis. The present study demonstrated that EZH2 promotes NSCLC progression through activation of the JAK2/STAT3 signaling pathway, identifying the EZH2-JAK2/STAT3 axis as a potential therapeutic vulnerability in this malignancy.