Blevins Melanie A, Towers Christina G, Patrick Aaron N, Zhao Rui, Ford Heide L
University of Colorado Anschutz Medical Campus, Department of Biochemistry and Molecular Genetics , Aurora, CO 80045 , USA
Expert Opin Ther Targets. 2015 Feb;19(2):213-25. doi: 10.1517/14728222.2014.978860. Epub 2015 Jan 2.
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.
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.
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.
六种同源结构域蛋白和无眼（EYA）共激活因子家族形成一种二元转录因子复合物，该复合物在器官发生过程中促进祖细胞的增殖和存活，且在大多数成年组织中表达下调。成年组织中SIX1和EYA的异常过表达与多种肿瘤类型的发生和进展相关。重要的是，SIX1和EYA在肿瘤中常共同过表达，并且在乳腺癌模型中，SIX1-EYA2相互作用已被证明对转移至关重要。EYA蛋白还具有蛋白酪氨酸磷酸酶活性，这在乳腺癌的生长和转移以及引导细胞在DNA损伤后进入修复途径中发挥重要作用。
本综述总结了与发育和疾病相关的SIX1/EYA复合物以及目前针对该复合物进行治疗靶向的研究进展。
最近，越来越多的研究表明，靶向SIX1/EYA转录复合物将有效抑制肿瘤进展。尽管目前开发针对该复合物抑制剂的尝试仍处于早期阶段，但持续努力开发更好的化合物最终可能会产生有效的抗癌疗法。
