Oncogenic IL7R is downregulated by histone deacetylase inhibitor in esophageal squamous cell carcinoma via modulation of acetylated FOXO1
Oncogenic IL7R is downregulated by histone deacetylase inhibitor in esophageal squamous cell carcinoma via modulation of acetylated FOXO1
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DOI：
10.3892/ijo.2018.4392
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发表时间：
2018-07-01
影响因子：
5.2
通讯作者：
You, Jueng Soo
中科院分区：
文献类型：
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作者：
Kim, Myoung Jun;Choi, Sung Kyung;You, Jueng Soo
白细胞介素-7受体（IL 7 R）通常在免疫细胞中表达，并且在免疫系统的存活、发育和稳态中至关重要。近年来，全基因组肿瘤研究发现IL-7 R在食管鳞状细胞癌（esophageal squamous cell carcinoma，ESCC）中存在基因扩增现象，但IL-7 R在ESCC中的确切作用尚不清楚。在本研究中，发现IL 7 R在ESCC组群中过表达，并且IL 7 R的丧失在ESCC细胞系中诱导抗癌作用。筛选了一小组表观遗传药物下调IL 7 R表达的能力。出乎意料的是，apicidin，组蛋白脱乙酰酶（HDAC）抑制剂，有效地下调IL 7 R的表达在早期的时间点，在剂量依赖性的方式，通过定量聚合酶链反应和IL 7 R免疫染色，并不需要从头蛋白质合成。值得注意的是，apicidin诱导含叉头盒蛋白，O亚家族1的乙酰化，其作为IL 7 R启动子的阻遏物，伴随着基于染色质免疫沉淀测定的耗尽的活性组蛋白修饰。综上所述，这些结果表明，通过HDAC抑制剂靶向ESCC中的致癌IL 7 R可能是一种有价值的治疗方法。
The interleukin-7 receptor (IL7R) is generally expressed in immune cells and is critical in survival, development and homeostasis in the immune system. Advanced genome-wide cancer studies have reported that IL7R is genetically amplified in human esophageal squamous cell carcinoma (ESCC), however, the exact role of IL7R in ESCC has not been investigated. In the present study, it was found that IL7R was overexpressed in ESCC cohorts and the loss of IL7R induced anti-oncogenic effects in ESCC cell lines. A small panel of epigenetic drugs were screened for their ability to downregulate the expression of IL7R. Unexpectedly, apicidin, a histone deacetylase (HDAC) inhibitor, effectively downregulated the expression of IL7R in a dose-dependent manner at an early time-point, as determined by quantitative polymerase chain reaction and IL7R immunostaining, and did not require de novo protein synthesis. Of note, apicidin induced the acetylation of Forkhead box-containing protein, O subfamily 1, which acts as a repressor at the IL7R promoter, accompanied with depleted active histone modifications based on chromatin immunoprecipitation assay. Taken together, these results demonstrated that targeting oncogenic IL7R in ESCC by HDAC inhibitors may be a valuable therapeutic approach.