The SIX1-EYA transcriptional complex as a therapeutic target in cancer

Abstract

Introduction: The SIX homeodomain proteins and the eyes absent (EYA) family of co-activators form a bipartite transcription factor complex that promotes the proliferation and survival of progenitor cells during organogenesis and is down-regulated in most adult tissues. Abnormal over-expression of SIX1 and EYA in adult tissue is associated with the initiation and progression of diverse tumor types. Importantly, SIX1 and EYA are often co-overexpressed in tumors, and the SIX1-EYA2 interaction has been shown to be critical for metastasis in a breast cancer model. The EYA proteins also contain protein tyrosine phosphatase activity, which plays an important role in breast cancer growth and metastasis as well as directing cells to the repair pathway upon DNA damage.

Areas covered: This review provides a summary of the SIX1/EYA complex as it relates to development and disease and the current efforts to therapeutically target this complex.

Expert opinion: Recently, there have been an increasing number of studies suggesting that targeting the SIX1/EYA transcriptional complex will potently inhibit tumor progression. Although current attempts to develop inhibitors targeting this complex are still in the early stages, continued efforts toward developing better compounds may ultimately result in effective anti-cancer therapies.

Keywords: inhibition of transcriptional complexes; metastasis; phosphatase; protein–protein interaction; six1/eyes absent complex; transcription factor.

Figure 1

A recreation of the Cancer Hallmarks, illustrating the known hallmarks in which the SIX1 and EYA family members carry out their tumor-promoting properties. In total, the SIX1/EYA complex has been shown to play a role in four out of the six original hallmarks, one of the two enabling characteristics and one of the two emerging hallmarks, highlighting the importance of targeting this complex as a potential therapeutic.

Figure 2

Surface representation illustrating the similarities between the protein interfaces of SIX1/EYA2 and two successfully targeted protein interactions, P53/MDM2 and BAK/BCL-XL. The red ribbon represents the single helix in SIX1, P53, and BAK that interacts with their corresponding protein partners in blue.

Figure 3

Chemical structures of the 3 series of compounds identified as inhibitors of EYA2 phosphatase activity. A. Benzbromarone and benzarone identified through the screening of a small NCI library. B. Two representative Mg²⁺ chelators identified through virtual screening. C. The top two allosteric N-arylidenebenzohydrazide compounds identified through a large scale HTS.