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.

Yanan Zhang,Bo Wei,Yuhua Song,Jiaxiu Xiong,Xiaoli Luo,Qinong Ye,Yingjie Chen,Xiaojie Xu,Zhida Chen,Lihua Ding,Jing Lin,Jie Liu,Lei Zhou

doi:10.18632/oncotarget.7126

Abstract

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.

Highlights

Angiogenesis is essential for cancer development and progression since adequate blood supply is necessary for cancer cell growth and metastasis [1, 2]
GATA1 did not interact with HIF1α HIF1α interacted with four and a half LIM protein 1 (FHL1) as we previously reported [49] (Supplementary Figure S7C). These results suggest that GATA1, SET7, polymerase II (Pol II), and TFIIB may form a preinitiation complex on the GATC site of Vascular endothelial growth factor (VEGF) promoter
Our study documents a functional role for transcription factor GATA1 in recruiting the histone methyltransferase SET7 to specific gene targets, such as VEGF

Summary

Introduction

Angiogenesis is essential for cancer development and progression since adequate blood supply is necessary for cancer cell growth and metastasis [1, 2]. The expression of VEGF can be regulated at the transcriptional level through the binding of transcription factors and RNA polymerase II (Pol II) to VEGF promoter [11, 12]. Transcriptional regulation of VEGF occurs via the core promoter, the minimal portion of the promoter required to properly initiate transcription, and other regulatory elements, including proximal and distal promoters. Transcription factors, such as specific activator 1 (SP1), hypoxia-inducible factor 1 (HIF1α) and signal transducers and activators of transcription 3 www.impactjournals.com/oncotarget (STAT3) [13,14,15], have been shown to regulate VEGF transcription, how the VEGF core promoter is controlled by sequence-specific transcription factors remains largely unknown. How transcription factors orchestrate the recruitment of histone modifying enzymes to VEGF promoter is unclear

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Conclusion