Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Division of Gastrointestinal Cancer Translational Research Laboratory, Peking University Cancer Hospital & Institute, Beijing, China.
Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing, China.
Cell Death Dis. 2019 Jan 15;10(2):33. doi: 10.1038/s41419-018-1278-2.
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.
ISL1 是 LIM 同源结构域转录因子，作为多种肿瘤转移的标志物。然而，ISL1 在胃癌（GC）中的功能和潜在机制尚未完全阐明。在这里，我们发现 ISL1 在 GC FFPE 样本中频繁过表达（104/196，53.06%），并与更差的临床结局相关。此外，ISL1 的过表达和功能丧失会影响体外和体内的细胞增殖、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 来确定 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）的关键调节剂。同时，我们通过影响 H3K4me3 验证了 ISL1 作为 ZEB1 启动子的激活子。我们证实，ISL1 和 SETD7（一种组蛋白 H3K4 特异性甲基转移酶）之间的复合物可以直接结合到 ZEB1 启动子上，通过免疫沉淀、质谱和 ChIP-re-ChIP 在 GC 细胞中激活其表达。此外，ZEB1 的表达与 ISL1 显著正相关，并与原发性 GC 标本的不良预后相关。我们的论文揭示了 ISL1 通过与共因子 SETD7 结合到 ZEB1 启动子来促进 GC 转移的分子机制。ISL1 可能是 GC 的潜在预后生物标志物。
