Eyes absent gene (EYA1) is a pathogenic driver and a therapeutic target for melanoma
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Joshua Jiawei Zhou1,2, Yuanshen Huang3, Xue Zhang3, Yabin Cheng4, Liren Tang2 and Xiaodong Ma5
1Department of Anesthesiology, Pharmacology, and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
2Welichem Biotech Inc., Burnaby, BC, Canada
3Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
4School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China
5College of Pharmacology, Dalian Medical University, Dalian, Liaoning Province, China
Liren Tang, email: firstname.lastname@example.org
Xiaodong Ma, email: email@example.com
Yabin Cheng, email: firstname.lastname@example.org
Keywords: melanoma, biomarker, EYA1, chromatin remodeling, benzbromarone
Received: June 01, 2017 Accepted: August 28, 2017 Published: September 27, 2017
EYA1 is a DNA repair enzyme that is induced after DNA damage and is upregulated in melanoma. However, its role in pathogenesis and therapeutic targeting of melanoma is unknown. Our objectives are (1) to study the relationship between EYA1 expression levels and melanoma patients’ clinical pathologic parameters including survival; (2) to investigate its impact on cultured melanoma cells in vitro; and (3) to evaluate EYA1 inhibitors’ potential as a treatment of melanoma.
Melanoma tissue microarrays were used to assess EYA1 protein expression in 326 melanoma tissues, and to correlate the expression with patients’ clinical pathological parameters. In addition, retroviral ShRNA vectors were used to silence expression of EYA1 in A375 melanoma cells, and the resultant cells examined for changes in growth, DNA synthesis, and tumor formation in vitro. Lastly, melanoma cells were treated with benzbromarone with or without the BRAF inhibitor vemurafenib.
Our results showed that EYA1 protein is low in benign nevi, but is significantly up-regulated in melanoma in situ, and remains high in invasive and metastatic melanoma. In addition, silencing of EYA1 gene expression resulted in decreased proliferation and colony formation. These were associated with decreased cyclin D1 and increased phosphorylated histone protein γH2AX. Finally, treatment with benzbromarone, a specific inhibitor of EYA1, caused significant inhibition of melanoma cell proliferation, and increased sensitivity to the BRAF inhibitor vemurafenib.
In conclusion, EYA1 gene is a pathogenic driver in melanoma pathogenesis. Targeting EYA1 may be a valuable strategy for treatment of melanoma.
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