The transcription factor GATA1 and the histone methyltransferase SET7 interact to promote VEGF-mediated angiogenesis and tumor growth and predict clinical outcome of breast cancer.
The transcription factor GATA1 and the histone methyltransferase SET7 interact to promote VEGF-mediated angiogenesis and tumor growth and predict clinical outcome of breast cancer.
复制标题
转录因子 GATA1 和组蛋白甲基转移酶 SET7 相互作用促进 VEGF 介导的血管生成和肿瘤生长并预测乳腺癌的临床结果
DOI：
10.18632/oncotarget.7126
复制
发表时间：
2016-03-01
期刊：
影响因子：
--
通讯作者：
Ye Q
中科院分区：
文献类型：
--
作者：
Zhang Y;Liu J;Lin J;Zhou L;Song Y;Wei B;Luo X;Chen Z;Chen Y;Xiong J;Xu X;Ding L;Ye Q
血管生成对肿瘤的生长至关重要。血管内皮生长因子(VEGF)是肿瘤血管生成最重要的调节因子。然而，转录因子如何与组蛋白修饰酶相互作用来调节血管内皮生长因子的转录和肿瘤血管生成仍不清楚。在这里，我们发现转录因子GATA1与组蛋白甲基转移酶Set7结合，促进血管内皮生长因子的转录和乳腺肿瘤血管生成。通过染色质免疫沉淀实验，我们发现GATA1是将Set7、RNA聚合酶II和转录因子II B募集到血管内皮生长因子核心启动子所必需的。GATA1通过Set7促进乳腺癌细胞(MCF7、ZR75-1和MDA-MB-231)分泌VEGF，促进血管内皮细胞(HUVEC)增殖、迁移和管状形成。在GATA1诱导的乳腺肿瘤血管生成和裸鼠体内生长中，Set7是必需的。免疫组织化学染色显示80例乳腺癌组织中GATA1和Set7表达上调，并与VEGF表达和微血管数呈正相关。GATA1和Set7是独立的乳腺癌预后不良因素。我们的数据为血管内皮生长因子转录调控提供了新的见解，并建议将GATA1/Set7作为癌症治疗的靶点。
Angiogenesis is essential for tumor growth. Vascular endothelial growth factor (VEGF) is the most important regulator of tumor angiogenesis. However, how transcription factors interact with histone-modifying enzymes to regulate VEGF transcription and tumor angiogenesis remains unclear. Here, we show that transcription factor GATA1 associates with the histone methyltransferase SET7 to promote VEGF transcription and breast tumor angiogenesis. Using chromatin immunoprecipitation assay, we found that GATA1 was required for recruitment of SET7, RNA polymerase II and transcription factor II B to VEGF core promoter. GATA1 enhanced breast cancer cell (MCF7, ZR75-1 and MDA-MB-231)-secreted VEGF via SET7, which promoted vascular endothelial cell (HUVEC) proliferation, migration and tube formation. SET7 was required for GATA1-induced breast tumor angiogenesis and growth in nude mice. Immunohistochemical staining showed that expression of GATA1 and SET7 was upregulated and positively correlated with VEGF expression and microvessel number in 80 breast cancer patients. GATA1 and SET7 are independent poor prognostic factors in breast cancer. Our data provide novel insights into VEGF transcriptional regulation and suggest GATA1/SET7 as cancer therapeutic targets.