EZH2 promotes tumor progression via regulating VEGF-A/AKT signaling in non-small cell lung cancer

•  EZH2, as an independent prognostic factor, correlates positively with VEGF-A. 
•  EZH2 overexpression confers a shorter overall survival time in NSCLC patients. 
•  EZH2 stimulates VEGF-A expression and the aggressiveness of lung cancer cells. 
•  VEGF-A induces AKT phosphorylation without affecting the EZH2 activity. 
•  EZH2 promotes tumor progression via the PI3K/AKT pathway in NSCLC.

Enhancer of Zeste Homologue 2 (EZH2) accounts for aggressiveness and unfavorable prognosis of tumor. We investigated the mechanisms and signaling pathways of EZH2 in non-small cell lung carcinoma (NSCLC) progression. Increased expression of EZH2, vascular endothelial growth factor-A (VEGF-A) and AKT phosphorylation correlated with differentiation, lymph node metastasis, size and TNM stage in NSCLC. There was a positive correlation between EZH2 and VEGF-A expression and high EZH2 expression, as an independent prognostic factor, predicted a shorter overall survival time for NSCLC patients. The expression of VEGF-A and phosphorylated Ser473-AKT, cell proliferation, migration and metastasis were enhanced in EZH2-overexpressing A549 cells, but inhibited in parental H2087 cells with EZH2 silencing or GSK126 treatment. AKT activity was enhanced by recombinant human VEGF-165 but suppressed by bevacizumab. An AKT inhibitor MK-2206 blocked VEGF-A expression and AKT phosphorylation in parental H2087 and EZH2-overexpressing A549 cells. EZH2 activity was not affected by either VEGF-A stimulation/depletion or MK-2206 inhibition. These results demonstrate that EZH2 promotes lung cancer progression via the VEGF-A/AKT signaling pathway.