Epithelial Splicing Regulatory Proteins 1 (ESRP1) and 2 (ESRP2) Suppress Cancer Cell Motility via Different Mechanisms

Background: The roles of ESRP1 and ESRP2 during carcinogenesis remain unknown. Results: ESRPs are up-regulated during carcinogenesis but down-regulated in invasive fronts. ESRP1 suppresses expression of the Rac1b isoform, whereas ESRP2 represses epithelial-mesenchymal transition-inducing transcription factors. Conclusion: ESRP1 and ESRP2 suppress cell motility through distinct transcriptional and/or post-transcriptional mechanisms. Significance: Our findings reveal a novel molecular network that regulates cancer cell motility. ESRP1 (epithelial splicing regulatory protein 1) and ESRP2 regulate alternative splicing events associated with epithelial phenotypes of cells, and both are down-regulated during the epithelial-mesenchymal transition. However, little is known about their expression and functions during carcinogenesis. In this study, we found that expression of both ESRP1 and ESRP2 is plastic: during oral squamous cell carcinogenesis, these proteins are up-regulated relative to their levels in normal epithelium but down-regulated in invasive fronts. Importantly, ESRP1 and ESRP2 are re-expressed in the lymph nodes, where carcinoma cells metastasize and colonize. In head and neck carcinoma cell lines, ESRP1 and ESRP2 suppress cancer cell motility through distinct mechanisms: knockdown of ESRP1 affects the dynamics of the actin cytoskeleton through induction of Rac1b, whereas knockdown of ESRP2 attenuates cell-cell adhesion through increased expression of epithelial-mesenchymal transition-associated transcription factors. Down-regulation of ESRP1 and ESRP2 is thus closely associated with a motile phenotype of cancer cells.