Snail Represses the Splicing Regulator Epithelial Splicing Regulatory Protein 1 to Promote Epithelial-Mesenchymal Transition

• Published in: The Journal of biological chemistry 2012-10, Vol.287 (43), p.36435-36442
• Main Authors: Reinke, Lauren M., Xu, Yilin, Cheng, Chonghui
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Alternative Splicing - physiology; Animals; CD44; Cell Line, Tumor; Dogs; EMT; Epithelial-Mesenchymal Transition - physiology; ESRP1; Exons - physiology; Gene Regulation; HEK293 Cells; Humans; Hyaluronan Receptors - biosynthesis; Hyaluronan Receptors - genetics; Protein Isoforms - biosynthesis; Protein Isoforms - genetics; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA; RNA-Binding Proteins - biosynthesis; RNA-Binding Proteins - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.397125

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. Background: The Epithelial Splicing Regulatory Protein 1 (ESRP1) prevents CD44 splice isoform switching during epithelial-mesenchymal transition (EMT), a developmental process frequently reactivated in cancer progression. Results: Snail represses ESRP1 transcription, thus promoting CD44 isoform switching during EMT. Conclusion: Repression by Snail of ESRP1 transcription is required for EMT to occur. Significance: Investigating mechanisms that regulate alternative splicing during EMT will facilitate our understanding of the EMT associated with cancer recurrence and metastasis.