ISL1 predicts poor outcomes for patients with gastric cancer and drives tumor progression through binding to the ZEB1 promoter together with SETD7
ISL1 predicts poor outcomes for patients with gastric cancer and drives tumor progression through binding to the ZEB1 promoter together with SETD7
复制标题
ISL1 预测胃癌患者的不良预后，并通过与 SETD7 结合到 ZEB1 启动子来驱动肿瘤进展
DOI：
10.1038/s41419-018-1278-2
复制
发表时间：
2019-01-15
影响因子：
9
通讯作者：
Ji, Jia-Fu
中科院分区：
文献类型：
--
作者：
Guo, Ting;Wen, Xian-Zi;Ji, Jia-Fu
ISL1是一种LIM同源结构域转录因子，是多种肿瘤转移的生物标志物。然而，Isl1在胃癌中的作用和机制尚未完全阐明。我们发现Isl1在GC FFPE组织中经常过表达(104/196，53.06%)，并与较差的临床预后相关。此外，Isl1的过度表达和功能的丧失在体内外影响细胞的增殖、侵袭和迁移，包括GC患者来源的异种移植模型。我们使用CHIP-SEQ和RNA-SEQ来鉴定Isl1影响H3K4甲基化的调节，并与ZEB1结合，ZEB1是上皮-间充质转化(EMT)的关键调节因子。同时，我们通过影响H3K4me3来验证Isl1是否激活了ZEB1启动子。我们通过免疫沉淀、质谱学和芯片重芯片技术证实，Isl1和SETD7(组蛋白H3K4特异性甲基转移酶)之间的复合体可以直接与ZEB1启动子结合，激活ZEB1在GC细胞中的表达。此外，在原发胃癌标本中，ZEB1的表达与Isl1呈显著正相关，且与不良预后呈正相关。本论文揭示了ISL1通过与ZEB1启动子结合以及辅因子SETD7促进胃癌转移的分子机制。ISL1可能是一种潜在的胃癌预后生物标志物。
ISL1, a LIM-homeodomain transcription factor, serves as a biomarker of metastasis in multiple tumors. However, the function and underlying mechanisms of ISL1 in gastric cancer (GC) have not been fully elucidated. Here we found that ISL1 was frequently overexpressed in GC FFPE samples (104/196, 53.06%), and associated with worse clinical outcomes. Furthermore, the overexpression of ISL1 and loss-of-function of ISL1 influenced cell proliferation, invasion and migration in vitro and in vivo, including GC patient-derived xenograft models. We used ChIP-seq and RNA-seq to identify that ISL1 influenced the regulation of H3K4 methylation and bound to ZEB1, a key regulator of the epithelial–mesenchymal transition (EMT). Meanwhile, we validated ISL1 as activating ZEB1 promoter through influencing H3K4me3. We confirmed that a complex between ISL1 and SETD7 (a histone H3K4-specific methyltransferase) can directly bind to the ZEB1 promoter to activate its expression in GC cells by immunoprecipitation, mass spectrometry, and ChIP-re-ChIP. Moreover, ZEB1 expression was significantly positively correlated with ISL1 and was positively associated with a worse outcome in primary GC specimens. Our paper uncovers a molecular mechanism of ISL1 promoting metastasis of GC through binding to the ZEB1 promoter together with co-factor SETD7. ISL1 might be a potential prognostic biomarker of GC.