Structure-Function Analyses of the Human SIX1–EYA2 Complex Reveal Insights into Metastasis and BOR Syndrome

SIX1 interacts with EYA to form a bipartite transcription factor essential for development. Loss of function of this complex causes branchio-oto-renal syndrome (BOR), while re-expression of SIX1 or EYA promotes metastasis. Here we describe the 2.0 Å structure of SIX1 bound to EYA2, which suggests a novel DNA binding mechanism for SIX1 and provides a rationale for the effect of BOR syndrome mutations. The structure also reveals that SIX1 uses predominantly a single helix to interact with EYA. Substitution of a single amino acid in this helix is sufficient to disrupt the SIX1–EYA interaction, SIX1-mediated epithelial-mesenchymal transition and metastasis in mouse models. Given that SIX1 and EYA are co-overexpressed in many tumor types, our data indicate that targeting the SIX1–EYA complex may be a potent approach to inhibit tumor progression in multiple cancer types.