Division of Hematology and Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
J Biol Chem. 2012 Oct 19;287(43):36435-42. doi: 10.1074/jbc.M112.397125. Epub 2012 Sep 7.
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.
上皮-间充质转化（EMT）是一个受到严格调控的过程，对发育至关重要，在癌症转移和复发过程中经常被重新激活。我们之前曾报道过 CD44 异构体转换对于 EMT 是至关重要的，并表明剪接因子 ESRP1 在 EMT 过程中抑制 CD44 异构体转换。然而，ESRP1 在 EMT 过程中的调控机制尚未完全理解。在这里，我们表明转录抑制因子 Snail 结合到 ESRP1 启动子中的 E 盒，导致 ESRP1 基因的抑制。从生物化学角度来看，我们定义了 ESRP1 调节 CD44 可变剪接的机制：ESRP1 结合到 CD44 可变外显子侧翼的内含子区域，导致可变外显子的包含增加。我们进一步表明，异位表达 ESRP1 抑制 Snail 诱导的 EMT，这表明 Snail 在 EMT 中的功能需要下调 ESRP1。总之，这些数据揭示了转录因子 Snail 通过调节剪接因子如何介导 EMT。
