Abstract
BackgroundThe aims of this study were to investigate the link between enhancer of zeste homolog 2 (EZH2) and histone deacetylase (HDAC) in preclinical studies and in human lung cancer tissue microarrays.MethodsEnhancer of zeste homolog 2 and HDAC1 mRNA expression in two lung adenocarcinoma (LUAD) datasets (MDACC and TCGA) were correlated with patient outcomes. We evaluated the association of EZH2 and HDAC1 expression with response to the HDAC1 inhibitor, suberoylanilide hydroxamic acid (SAHA). The response to SAHA was assessed at baseline and after alteration of EZH2 or HDAC mRNA expression in LUAD cell lines.ResultsDirect correlation was found between EZH2 and HDAC1 expression (P < 0.0001). When EZH2 expression was knocked down‐ or upregulated, there was a corresponding decrease or increase in expression of HDAC expression, respectively. Cell lines with high EZH2 expression responded to SAHA treatment with a mean inhibition rate of 73.1% compared to 43.2% in cell lines with low EZH2 expression (P < 0.0001). This correlation was confirmed in non‐small cell lung cancer (NSCLC) specimens from MDACC (Spearman's correlation r = 0.416; P < 0.0001) and TCGA datasets (r = 0.221; P < 0.0001). Patients with high EZH2 and high HDAC1 expression in stage I NSCLC specimens of both datasets had the lowest survival compared to the patients with low expression of either or both markers.ConclusionOur findings show that overexpression of EZH2 is a negative prognostic indicator. Increased EZH2 expression predicts for response to HDAC inhibitors and thus could serve as a biomarker for selecting NSCLC patients for treatment with HDAC inhibitors.
Highlights
Advances in our knowledge of the molecular pathways activated in lung cancer have led to the development of novel pathway‐directed targeted therapies
Given the interaction between enhancer of zeste homolog 2 (EZH2) and histone deacetylase (HDAC), we evaluated the link between EZH2 expression and response to HDAC inhibition in non‐small cell lung cancer (NSCLC) cell lines and explored the feasibility of using EZH2 expression as a biomarker of response to HDAC inhibitors in human tumors
Our cell line results are corroborated by our previously reported clinical data[13] where we have shown that EZH2 expression both at the mRNA level and the protein level was correlated with smoking status with current or former smokers having higher expression levels compared to never smokers (P = 0.001)
Summary
Advances in our knowledge of the molecular pathways activated in lung cancer have led to the development of novel pathway‐directed targeted therapies. H3K27 is functionally activated in the methylated state.[3] Enhancer of zeste homolog 2 is upregulated in several of the most common malignancies, including lung cancer, and has been demonstrated to be a negative prognostic marker.[4,5]. Methods: Enhancer of zeste homolog 2 and HDAC1 mRNA expression in two lung adenocarcinoma (LUAD) datasets (MDACC and TCGA) were correlated with patient outcomes. Cell lines with high EZH2 expression responded to SAHA treatment with a mean inhibition rate of 73.1% compared to 43.2% in cell lines with low EZH2 expression (P < 0.0001) This correlation was confirmed in non‐small cell lung cancer (NSCLC) specimens from MDACC (Spearman’s correlation r = 0.416; P < 0.0001) and TCGA datasets (r = 0.221; P < 0.0001). Increased EZH2 expression predicts for response to HDAC inhibitors and could serve as a biomarker for selecting NSCLC patients for treatment with HDAC inhibitors
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