University of Texas MD Anderson Cancer Center, Houston, Texas.
University of Texas School of Biomedical Informatics, Houston, Texas.
Cancer Med. 2019 Oct;8(14):6383-6392. doi: 10.1002/cam4.1855. Epub 2019 Aug 27.
The 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.
Enhancer 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.
Direct 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.
Our 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.
本研究旨在探讨增强子结合锌指蛋白 2（EZH2）和组蛋白去乙酰化酶（HDAC）在临床前研究和人类肺癌组织微阵列中的关联。
在两个肺腺癌（LUAD）数据集（MDACC 和 TCGA）中，EZH2 和 HDAC1mRNA 的表达与患者的预后相关。我们评估了 EZH2 和 HDAC1 表达与对 HDAC1 抑制剂 suberoylanilide hydroxamic acid（SAHA）的反应之间的关联。在 LUAD 细胞系中，在改变 EZH2 或 HDAC mRNA 表达前后，评估对 SAHA 的反应。
发现 EZH2 和 HDAC1 表达之间存在直接相关性（P<0.0001）。当 EZH2 表达被敲低或上调时，HDAC 表达分别相应地减少或增加。EZH2 表达高的细胞系对 SAHA 治疗的平均抑制率为 73.1%，而 EZH2 表达低的细胞系为 43.2%（P<0.0001）。这一相关性在 MDACC 的非小细胞肺癌（NSCLC）标本（Spearman 相关 r=0.416；P<0.0001）和 TCGA 数据集（r=0.221；P<0.0001）中得到了证实。在两个数据集的 I 期 NSCLC 标本中，EZH2 和 HDAC1 高表达的患者与表达水平低或两者均低的患者相比，生存率最低。
我们的研究结果表明，EZH2 的过度表达是一个负面的预后指标。EZH2 表达增加预示着对 HDAC 抑制剂的反应，因此可以作为选择 NSCLC 患者接受 HDAC 抑制剂治疗的生物标志物。
