Abstract
BackgroundEpigenetic silencing is a common mechanism to inactivate tumor suppressor genes during carcinogenesis. Enhancer of Zeste 2 (EZH2) is the histone methyltransferase subunit in polycomb repressive complex 2 which mediates transcriptional repression through histone methylation. EZH2 overexpression has been linked to aggressive phenotypes of certain cancers. However, the mechanism that EZH2 played in promoting malignancy in non-small cell lung cancer (NSCLC) remains unclear. In addition, the correlation of EZH2 overexpression and the prognosis of NSCLC patients in non-Asian cohort need to be determined.Methodology/Principal FindingsUp-regulation of EZH2 was found in NSCLC cells compared with normal human bronchial epithelial cells by western blot assay. Upon EZH2 knockdown using small interfering RNA (siRNA), the proliferation, anchorage-independent growth and invasion of NSCLC cells were remarkably suppressed with profound induction of G1 arrest. Furthermore, the expression of cyclin D1 was notably reduced whereas p15INK4B, p21Waf1/Cip1 and p27Kip1 were increased in NSCLC cells after EZH2-siRNA delivery. To determine whether EZH2 expression contributes to disease progression in patients with NSCLC, Taqman quantitative real-time RT-PCR was used to measure the expression of EZH2 in paired tumor and normal samples. Univariate analysis revealed that patients with NSCLC whose tumors had a higher EZH2 expression had significantly inferior overall, disease-specific, and disease-free survivals compared to those whose tumors expressed lower EZH2 (P = 0.005, P = 0.001 and P = 0.003, respectively). In multivariate analysis, EZH2 expression was an independent predictor of disease-free survival (hazard ratio = 0.450, 95% CI: 0.270 to 0.750, P = 0.002).Conclusions/SignificanceOur results demonstrate that EZH2 overexpression is critical for NSCLC progression. EZH2 mRNA levels may serve as a prognostic predictor for patients with NSCLC.
Highlights
Lung cancer is the leading cause of cancer-related deaths in the United States, it kills more that 160,000 Americans each year [1], of which, non-small cell lung cancer (NSCLC) accounts for more than 85% of the cases
Transfection of si-4916 in these NSCLC cells resulted in 10–60% reduction of EZH2 expression, whereas transfection with si-4917 reduced EZH2 protein level by 70–80% (Fig. 1C)
The results showed that reducing EZH2 expression lead to the accumulation of the cells in G1 phase and the reduction of cells in S phase (Fig. 2C and 2D)
Summary
Lung cancer is the leading cause of cancer-related deaths in the United States, it kills more that 160,000 Americans each year [1], of which, non-small cell lung cancer (NSCLC) accounts for more than 85% of the cases. Understanding the molecular mechanism of cancer progression is critical for advancing the treatment of lung cancer [5,6,7]. Methylation of CpG islands in the promoter regions is a common epigenetic mechanism to inactivate tumor suppressor genes, such as p16, PTEN, DAPK [8,9]. EZH2 is a member of PcG proteins and part of the polycomb repressor complex (PRC) 2 which methylates histone H3 at lysine 27 (H3K27Me3). Epigenetic silencing is a common mechanism to inactivate tumor suppressor genes during carcinogenesis. The mechanism that EZH2 played in promoting malignancy in non-small cell lung cancer (NSCLC) remains unclear. The correlation of EZH2 overexpression and the prognosis of NSCLC patients in non-Asian cohort need to be determined
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