The Protein Tyrosine Phosphatase Activity of Eyes Absent Contributes to Tumor Angiogenesis and Tumor Growth.

Abstract

DNA damage repair capacity is required for cells to survive catastrophic DNA damage and proliferate under conditions of intratumoral stress. The ability of the minor histone protein H2AX to serve as a hub for the assembly of a productive DNA damage repair complex is a necessary step in preventing DNA damage-induced cell death. The Eyes Absent (EYA) proteins dephosphorylate the terminal tyrosine residue of H2AX, thus permitting assembly of a productive DNA repair complex. Here, we use genetic and chemical biology approaches to separately query the roles of host vascular endothelial cell and tumor cell EYA in tumor growth. Deletion of Eya3 in host endothelial cells significantly reduced tumor angiogenesis and limited tumor growth in xenografts. Deletion of Eya3 in tumor cells reduced tumor cell proliferation and tumor growth without affecting tumor angiogenesis. A chemical inhibitor of the EYA tyrosine phosphatase activity inhibited both tumor angiogenesis and tumor growth. Simultaneously targeting the tumor vasculature and tumor cells is an attractive therapeutic strategy because it could counter the development of the more aggressive phenotype known to emerge from conventional antiangiogenic agents. Mol Cancer Ther; 17(8); 1659-69. ©2018 AACR.