Spleen tyrosine kinase SYK(L) interacts with YY1 and coordinately suppresses SNAI2 transcription in lung cancer cells
Spleen tyrosine kinase SYK(L) interacts with YY1 and coordinately suppresses SNAI2 transcription in lung cancer cells
复制标题
脾酪氨酸激酶 SYK(L) 与 YY1 相互作用并协同抑制肺癌细胞中 SNAI2 转录
DOI：
10.1111/febs.14665
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发表时间：
2018-11-01
期刊：
影响因子：
5.4
通讯作者：
Ma, Zhenyi
中科院分区：
文献类型：
--
作者：
Gao, Dan;Wang, Lingling;Ma, Zhenyi
脾酪氨酸激酶(SYK)是一种非受体酪氨酸激酶，在不同的细胞类型中具有癌蛋白和肿瘤抑制因子的双重性质。在实体瘤中，由于其选择性的基因剪接，最近发现了SYK的两种亚型：SYK(L)和SYK(S)。然而，在人类肺癌中，SYK(L)的长亚型SYK的细胞活性和生物学意义仍不是很清楚。在这里，我们描述了SYK(L)与细胞核中普遍表达的转录调节因子阴阳1(YY1)之间的相互作用，它通过抑制SNAI2(编码转录因子slug)转录来抑制上皮到间充质的转变。CHIP表明，内源性SYK(L)直接与SNAI2启动子中YY1结合的顺式调控元件相互作用。重要的是，YY1基因的敲除激活了人肺癌H1155细胞中SYK(L)依赖的EMT抑制。我们还发现，SYK(L)蛋白在不同类型的人肺癌中显著上调，其核定位与肺腺癌的临床疗效密切相关。总而言之，我们的数据揭示了依赖SYK(L)通过Slug对EMT的转录调控，作为肺癌侵袭性的潜在生物标记物。
Spleen tyrosine kinase (SYK) is a nonreceptor tyrosine kinase with dual properties of an oncoprotein and an oncosuppressor in distinctive cell types. In solid cancers, two isoforms SYK(L) and SYK(S) of SYK were recently identified due to its alternative mRNA splicing. However, the cellular activity and the biological significance of the long isoform of SYK, SYK(L), is still not well defined in human lung cancers. Here, we describe an interaction between SYK(L) and the ubiquitously expressed transcription regulator Yin Yang 1 (YY1) in the nucleus, which suppresses the epithelial‐to‐mesenchymal transition (EMT) by inactivating SNAI2 (coding transcription factor SLUG) transcription. ChIP indicated that endogenous SYK(L) interacts directly with a YY1 binding cis‐regulatory element in the SNAI2 promoter. Importantly, knockdown of YY1 activates SYK(L)‐dependent EMT suppression in human lung cancer H1155 cells. We also found that the protein level of SYK(L) is markedly upregulated in various types of human lung cancers, and its nuclear localization is strongly correlated with clinical benefits of lung adenocarcinomas. Collectively, our data reveal a SYK(L)‐dependent transcriptional regulation of EMT through SLUG as a potential biomarker for lung cancer aggressiveness.