Systems-level analysis identifies IRF6 as an inhibitor of epithelial-mesenchymal transition

BACKGROUND: Epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET) are crucial during metastasis and therapy resistance. While the dynamics and master regulators of EMT are well-studied, the transcription factors that can prevent EMT or promote MET are relatively less understood. RESULTS: Here, by integrating bulk and spatial transcriptomic data analysis from cell lines and patient samples with mechanism-based dynamical modelling we identify IRF6 as a factor that strongly associates with an epithelial phenotype and is often inhibited during EMT. In vitro experiments in multiple cancer cell lines demonstrate the progression to a mesenchymal phenotype upon IRF6 knockdown, suggesting a role as an inhibitor of EMT. Finally, we observe that IRF6 expression levels correlate with worse patient survival in a subset of solid tumour types. CONCLUSION: Our integrated computational-experimental, systems-level analysis suggests that IRF6 is frequently downregulated during EMT and can also prevent the progression towards a complete EMT, underscoring its role as an MET stabilizing factor.