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

Declaration of interest

The authors have been supported by grants from the Department of Defense Breast Cancer Program and Ovarian Cancer Program, the Breast Cancer Research Foundation-American Association for Cancer Research, State of Colorado, Cancer League of Colorado, Alex’s Lemonade Stand Foundation, The V Foundation for Cancer Research, The Sidney Kimmel Foundation, and the National Institute of Health (R03DA030559, R03DA033174, and R41CA180347 awarded to SixOne Solutions) to HL Ford and/or R Zhao. HL Ford is also funded by the National Cancer Institute (R01CA095277 and R01CA157790). MA Blevins is funded through the Paul Sandoval Pancreatic Cancer Scholarship. CG Towers has been supported by the UNCF/MERCK Graduate Fellowship and an R01 Diversity supplement. AN Patrick was supported by a Pediatric Hematology/Oncology Postdoctoral Fellowship (2T32082086-11A1). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

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