Sine oculis homeobox homolog 1–Eyes absent homolog 1 protein–protein interface (SIX1–EYA1 interface)

The SIX1–EYA1 protein–protein interface is a regulatory complex formed by the Sine oculis homeobox homolog 1 (SIX1) transcription factor and its co-activator, Eyes absent homolog 1 (EYA1). This interaction is vital for embryonic development, specifically in the organogenesis of the ears, kidneys, and branchial arches. In adult tissues, the complex is generally downregulated, but its aberrant reactivation is a hallmark of several cancers, including breast, lung, and colorectal carcinomas. When active, the SIX1–EYA1 complex drives oncogenic processes such as cell proliferation, survival, and the epithelial-mesenchymal transition (EMT), which facilitates metastasis. Mutations in the genes encoding these proteins are also linked to developmental disorders like Branchio-oto-renal (BOR) syndrome. As a therapeutic target, the interface is being explored for the development of small molecule inhibitors like NSC0191 and NSC0933, which disrupt the protein-protein interaction. These inhibitors aim to block the recruitment of EYA1 to SIX1-bound DNA sites, thereby inhibiting the expression of downstream targets like Cyclin A1 and TGF-beta. Targeting this specific interface is considered a promising anti-cancer strategy due to its limited expression in normal adult tissues, potentially reducing off-target toxicity.

Other names

SIX1-EYA1 complexSIX1-EYA1 interactionSIX1-EYA1 transcriptional complexSine oculis homeobox homolog 1–Eyes absent homolog 1 complex

Disruption of the protein-protein interaction between SIX1 and EYA1, preventing the formation of a functional transcriptional activation complex and inhibiting downstream oncogenic gene expression.