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

Abstract

Introduction The SIX homeodomain proteins and the 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 towards developing better compounds may ultimately result in effective anti-cancer therapies.

EYA4 Promotes Cell Proliferation Through Downregulation of p27Kip1 in Glioma

“…To determine whether EYA4 could bind to the p27Kip1 promoter in chromatin, a chromatin immunoprecipitation (ChIP) analysis was performed in U87MG cells. It has been reported that EYA protein can't directly bind to DNA, and it usually acts as a co-factor for the Six family proteins, which are transcription factors binding to DNA directly [8,27]. We found a putative Six1-binding site (GGGTATCA) in the promoter region of the p27Kip1 gene, at -1670 from the transcription star site.…”

SIX1 Oncoprotein as a Biomarker in a Model of Hormonal Carcinogenesis and in Human Endometrial Cancer

“…SIX1 overexpression is observed in a number of primary human cancers, where it is associated with recurrence, metastasis, resistance to standard chemotherapeutic agents, and decreased patient survival (22, 23, 29–33). Our findings in the mouse suggested that aberrant SIX1 expression could have a role in human endometrial cancer, but to date there are no published reports that have addressed this question.…”

“…SIX1 is a homeodomain-containing transcription factor that plays essential roles in mouse organogenesis by regulating cell proliferation, survival, migration, and invasion (21, 22). Indeed, it is considered an oncofetal protein because dysregulation and inappropriate re-expression result in genomic instability, malignant transformation, and metastasis in animal models and humans (21–23). Neonatal exposure to estrogenic chemicals not only causes a dramatic increase in Six1 transcript expression in the mouse uterus, but it also causes Six1 expression to become estrogen-responsive (19, 20).…”

A tale of two ends

“…Six1 expression is low or undetectable in most differentiated tissues, yet numerous studies have demonstrated elevated expression in tumors of multiple origins, where it is linked to metastatic disease. 3 Its pro-oncogenic functions include regulation of proliferation, survival, stem/progenitor cell functions, and in carcinomas, epithelial to mesenchymal transitions (EMT), 4 therefore closely mimicking its developmental roles.…”

“…Six1 expression results in decreased differentiation and an increase and/or maintenance of stem/progenitor cell populations in multiple tissue types. 4 Indeed, overexpression of a pool of 8 genes including Six1, Six2, and the Six1 co-activator, Eya1, reprograms adult cells to embryonic nephron progenitors. 6 In contrast, increased p53 has been strongly linked to a differentiated state.…”