Hoshino Isamu, Akutsu Yasunori, Murakami Kentaro, Akanuma Naoki, Isozaki Yuka, Maruyama Tetsuro, Toyozumi Takeshi, Matsumoto Yasunori, Suito Hiroshi, Takahashi Masahiko, Sekino Nobufumi, Komatsu Aki, Suzuki Takayoshi, Matsubara Hisahiro
Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Ann Surg Oncol. 2016 Jan;23(1):312-20. doi: 10.1245/s10434-015-4488-1. Epub 2015 Mar 20.
The expression of genes can be influenced by the balance of histone acetylation and/or histone demethylation, with an imbalance of these processes possibly observed in many cancers. The histone demethylase LSD1 inhibitor activity is associated with selective transcriptional regulation and alterations in the gene expression. However, the exact mechanisms underlying the antitumor effects of LSD1 inhibitors are not fully understood.
The antitumor effects of NCL1, an LSD1 inhibitor, in esophageal squamous cell cancer (ESCC) cell lines were evaluated. A comprehensive analysis of the changes in the gene expression in ESCC cell lines induced by NCL1 was carried out using a microarray analysis. A loss-of-function assay using a siRNA analysis was performed to examine the oncogenic function of the gene.
NCL1 strongly inhibited the cell growth of T.Tn and TE2 ESCC cells and induced apoptosis. According to the microarray analysis, 81 genes in the T.Tn cells and 149 genes in the TE2 cells were up- or down-regulated 2-fold or more by NCL1 exposure. Among these genes, 27 were contained in both cell lines and exhibited similar expression patterns. PHLDB2, one of the genes down-regulated by NCL1, was overexpressed in the ESCC tumor tissues. Moreover, a high expression level of PHLDB2 was found to be significantly correlated with poor prognosis.
The present observations of the comprehensive analysis of the gene expression levels provide insight into the mechanisms underlying the antitumor effects of LSD1 inhibitors in ESCC patients.
基因表达可受组蛋白乙酰化和/或组蛋白去甲基化平衡的影响，在许多癌症中可能观察到这些过程的失衡。组蛋白去甲基化酶LSD1抑制剂活性与选择性转录调控及基因表达改变相关。然而，LSD1抑制剂抗肿瘤作用的确切机制尚未完全明确。
评估LSD1抑制剂NCL1对食管鳞状细胞癌（ESCC）细胞系的抗肿瘤作用。使用微阵列分析对NCL1诱导的ESCC细胞系基因表达变化进行全面分析。采用小干扰RNA（siRNA）分析进行功能缺失实验，以检测该基因的致癌功能。
NCL1强烈抑制T.Tn和TE2 ESCC细胞的生长并诱导细胞凋亡。根据微阵列分析，NCL1处理后，T.Tn细胞中有81个基因、TE2细胞中有149个基因上调或下调2倍及以上。这些基因中，27个在两个细胞系中均有出现且表现出相似的表达模式。PHLDB2是NCL1下调的基因之一，在ESCC肿瘤组织中过表达。此外，发现PHLDB2的高表达水平与预后不良显著相关。
目前对基因表达水平的综合分析结果为深入了解LSD1抑制剂对ESCC患者的抗肿瘤作用机制提供了线索。
