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.

中文翻译：

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Eyes Absent 的蛋白酪氨酸磷酸酶活性有助于肿瘤血管生成和肿瘤生长

DNA 损伤修复能力是细胞在灾难性 DNA 损伤中存活并在肿瘤内应激条件下增殖所必需的。次要组蛋白 H2AX 作为组装生产性 DNA 损伤修复复合物的中心的能力是防止 DNA 损伤诱导的细胞死亡的必要步骤。Eyes Absent (EYA) 蛋白使 H2AX 的末端酪氨酸残基去磷酸化，从而允许组装生产性 DNA 修复复合物。在这里，我们使用遗传和化学生物学方法分别查询宿主血管内皮细胞和肿瘤细胞 EYA 在肿瘤生长中的作用。宿主内皮细胞中 Eya3 的缺失显着减少了肿瘤血管生成并限制了异种移植物中的肿瘤生长。肿瘤细胞中 Eya3 的缺失减少了肿瘤细胞增殖和肿瘤生长，而不影响肿瘤血管生成。EYA 酪氨酸磷酸酶活性的化学抑制剂抑制肿瘤血管生成和肿瘤生长。同时靶向肿瘤血管系统和肿瘤细胞是一种有吸引力的治疗策略，因为它可以对抗已知从常规抗血管生成剂中出现的更具侵略性的表型的发展。摩尔癌症治疗; 17(8); 1659-69 年。©2018 AACR。同时靶向肿瘤血管系统和肿瘤细胞是一种有吸引力的治疗策略，因为它可以对抗已知从常规抗血管生成剂中出现的更具侵略性的表型的发展。摩尔癌症治疗; 17(8); 1659-69 年。©2018 AACR。同时靶向肿瘤血管系统和肿瘤细胞是一种有吸引力的治疗策略，因为它可以对抗已知从常规抗血管生成剂中出现的更具侵略性的表型的发展。摩尔癌症治疗; 17(8); 1659-69 年。©2018 AACR。