Enhancer of zeste homolog 2 is a novel prognostic biomarker in nonsmall cell lung cancer

Abstract

BACKGROUND: Enhancer of zeste homolog 2 (EZH2) epigenetically silences many genes through the trimethylation of histone H3 lysine 27 and is implicated in tumor growth, invasion, and metastasis. However, its role in lung cancer has not been well characterized. The objective of the current study was to elucidate the role of EZH2 in nonsmall cell lung cancer (NSCLC) by investigating both clinical samples and cell lines. METHODS: An immunohistochemical analysis of EZH2 expression was performed in samples from patients with stage I NSCLC to investigate the association of EZH2 expression levels with clinicopathologic variables. An in vitro cell growth assay and a Matrigel invasion assay also were conducted in the EZH2-expressing NSCLC cell lines A549 and H1299 after knocking down EZH2 expression by using an EZH2-specific short-hairpin RNA. RESULTS: The immunohistochemical analysis classified stage I NSCLC samples (n ¼ 106) into a negative EZH2 expression group (n ¼ 40; 37.7%) and a positive EZH2 expression group (n ¼ 66; 62.3%). Positive EZH2 expression was associated significantly with larger tumor size (P ¼ .014). Kaplan-Meier survival analyses and log-rank tests demonstrated that patients whose samples were classified into the positive EZH2 expression group had a significantly shorter overall survival (P ¼ .015). Experiments in the NSCLC cell lines revealed that the knockdown of EZH2 expression reduced the tumor growth rate and invasive activity. CONCLUSIONS: The current results indicated that EZH2 promotes progression and invasion of NSCLC, and its expression is a novel prognostic biomarker in NSCLC. Cancer 2012;118:1599-

High expression of trimethylated histone H3 at lysine 27 predicts better prognosis in non-small cell lung cancer

“…It was reported that EZH2 was found to be overexpressed at both mRNA and protein levels in NSCLC and bladder cancer, and correlated with invasiveness, increased proliferation and poor outcome (20,21). In colorectal cancer, EZH2 overexpression indicated a good prognosis, in contrast to the poor prognosis associated with EZH2 overexpression in NSCLCs (20).…”

“…These proteins, together with the histone binding proteins retinoblastoma binding protein 4 (RBBP4) and RBBP7, comprise the core components of the polycomb repressive complex 2 (PRC2). Overexpression of EZH2 was also found in a variety of cancers, including lung cancer (20,21), breast cancer (5,(22)(23)(24)(25)(26), melanoma (27), colorectal (20) and pancreatic adenocarcinoma (28) and ovarian carcinoma (29), and turned out to be closely associated with high proliferation rate and aggressive tumor subgroups, resulting in worse clinical outcome thereafter. Although many reports on the role of H3K27me3 in carcinogenesis are available, its carcinogenic role in NSCLC and how it interacts with EZH2 and DNA methylation remain unclear.…”

Expanded molecular interrogation for potential actionable targets in non-squamous non-small cell lung cancer

“…EZH2 is overexpressed in NSCLC and is associated with poor prognosis (79,80). Similarly overexpression of HDACs has been observed in NSCLC (81).…”

Epigenetic Therapy for Cisplatin Resistance in Non-Small-Cell Lung Cancer: The way Forward?

“…One such member is EZH2 or KMT6. KMT6 is overexpressed in NSCLC with predictive and prognostic value [1,[9][10][11]. Knockdown of KMT6 has been shown to inhibit NSCLC proliferation, migration and invasion [9,10].…”

“…KMT6 is overexpressed in NSCLC with predictive and prognostic value [1,[9][10][11]. Knockdown of KMT6 has been shown to inhibit NSCLC proliferation, migration and invasion [9,10]. Overexpression of KMT6 occurs in cisplatin-resistant cell lines and knockdown results in enhanced sensitivity to cisplatin [10].…”