title: High expression of trimethylated histone H3 at lysine 27 predicts better prognosis in non-small cell lung cancer.
abstract: Epigenetic parameters such as DNA methylation and histone modifications play pivotal roles in carcinogenesis. Global histone modification patterns have been implicated as possible predictors of cancer recurrence and prognoses in a great variety of tumor entities. Our study was designed to evaluate the association among trimethylated histone H3 at lysine 27 (H3K27me3), clinicopathological variables and outcome in early-stage non-small cell lung cancer (NSCLC). The expression of H3K27me3 and its methyl-transferase, enhancer of zeste homolog 2 (EZH2) together with proliferating cell nuclear antigen (PCNA) were evaluated by immunohistochemistry in normal lung tissue (n=5) and resected NSCLC patients (n=42). In addition, the specificity of antibody for H3K27me3 was tested by western blot analysis. The optimal cut-off point of H3K27me3 expression for prognosis was determined by the X-tile program. The prognostic significance was determined by means of Kaplan-Meier survival estimates and log-rank tests. As a result, enhanced trimethylation of H3K27me3 was correlated with longer overall survival (OS) and better prognosis (P<0.05). Moreover, both univariate and multivariate analyses indicated that H3K27me3 level was a significant and independent predictor of better survival (hazard ratio, 0.187; 95% confidence interval, 0.066-0.531, P=0.002). Furthermore, H3K27me3 expression was positively correlated with DNA methylation level at CCGG sites while reversely related to EZH2 expression (P<0.05). In conclusion, H3K27me3 level defines unrecognized subgroups of NSCLC patients with distinct epigenetic phenotype and clinical outcome, and can probably be used as a novel predictor for better prognosis in NSCLC patients.
authors: Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan.
authors: Xiaohui
authors: X
authors: Chen
authors: Ning
authors: N
authors: Song
authors: Keitaro
authors: K
authors: Matsumoto
authors: Atsushi
authors: A
authors: Nanashima
authors: Takeshi
authors: T
authors: Nagayasu
authors: Tomayoshi
authors: T
authors: Hayashi
authors: Mingang
authors: M
authors: Ying
authors: Daisuke
authors: D
authors: Endo
authors: Zhiren
authors: Z
authors: Wu
authors: Takehiko
authors: T
authors: Koji
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000378:metabolism; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000378:metabolism; D019175:DNA Methylation; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008168:Lung / Q000378:metabolism*; D008175:Lung Neoplasms / Q000175:diagnosis / Q000378:metabolism; D008239:Lysine / Q000378:metabolism*; D008297:Male; D009367:Neoplasm Staging; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011379:Prognosis; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D008239:Lysine