Snail Represses the Splicing Regulator Epithelial Splicing Regulatory Protein 1 to Promote Epithelial-Mesenchymal Transition
Snail Represses the Splicing Regulator Epithelial Splicing Regulatory Protein 1 to Promote Epithelial-Mesenchymal Transition
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DOI：
10.1074/jbc.m112.397125
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发表时间：
2012-10-19
影响因子：
4.8
通讯作者：
Cheng, Chonghui
中科院分区：
文献类型：
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作者：
Reinke, Lauren M.;Xu, Yilin;Cheng, Chonghui
上皮-间质转化（Epithelial-mesenchymal transition， EMT）是一个受到严格调控的过程，对肿瘤的发育至关重要，在癌症转移和复发过程中经常被重新激活。我们之前报道过CD44异构体转换对EMT至关重要，并表明剪接因子ESRP1在EMT期间抑制CD44异构体转换。然而，在EMT过程中，ESRP1的调控机制尚不完全清楚。本研究表明，转录抑制因子Snail与ESRP1启动子中的e -box结合，导致ESRP1基因受到抑制。从生物化学角度，我们定义了ESRP1调控CD44选择性剪接的机制：ESRP1结合到CD44可变外显子侧翼的内含子区域，并导致可变外显子包含增加。我们进一步表明，异位表达ESRP1抑制蜗牛诱导的EMT，这表明ESRP1的下调是蜗牛在EMT中发挥功能所必需的。总之，这些数据揭示了转录因子Snail如何通过调节剪接因子介导EMT。
Epithelial-mesenchymal transition (EMT), a tightly regulated process that is critical for development, is frequently re-activated during cancer metastasis and recurrence. We reported previously that CD44 isoform switching is critical for EMT and showed that the splicing factor ESRP1 inhibits CD44 isoform switching during EMT. However, the mechanism by which ESRP1 is regulated during EMT has not been fully understood. Here we show that the transcription repressor Snail binds to E-boxes in the ESRP1 promoter, causing repression of the ESRP1 gene. Biochemically, we define the mechanism by which ESRP1 regulates CD44 alternative splicing: ESRP1 binds to the intronic region flanking a CD44 variable exon and causes increased variable exon inclusion. We further show that ectopically expressing ESRP1 inhibits Snail-induced EMT, suggesting that down-regulation of ESRP1 is required for function by Snail in EMT. Together, these data reveal how the transcription factor Snail mediates EMT through regulation of a splicing factor.