Transcriptional repression of VEGF by ZNF24: mechanistic studies and vascular consequences in vivo
- Authors
- Jia, D., Hasso, S.M., Chan, J., Filingeri, D., D'Amore, P.A., Rice, L., Pampo, C., Siemann, D.W., Zurakowski, D., Rodig, S.J., and Moses, M.A.
- ID
- ZDB-PUB-121206-49
- Date
- 2013
- Source
- Blood 121(4): 707-715 (Journal)
- Registered Authors
- Chan, Joanne
- Keywords
- none
- MeSH Terms
-
- Animals
- Binding Sites
- Blood Vessels/metabolism*
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism
- Cell Line, Tumor
- Female
- Gene Expression Regulation
- Humans
- Kruppel-Like Transcription Factors/genetics
- Kruppel-Like Transcription Factors/metabolism*
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Promoter Regions, Genetic
- Protein Binding
- Repressor Proteins/genetics
- Repressor Proteins/metabolism*
- Transcriptional Activation
- Vascular Endothelial Growth Factor A/genetics*
- Vascular Endothelial Growth Factor A/metabolism
- Zebrafish
- PubMed
- 23212515 Full text @ Blood
VEGF is a key regulator of normal and pathological angiogenesis. Although many trans-activating factors of VEGF have been described, the transcriptional repression of VEGF remains much less understood. We have previously reported the identification of a SCAN domain-containing C2H2 zinc finger protein, ZNF24, that represses the transcription of VEGF. Here, we identify the mechanism by which ZNF24 represses VEGF transcription. Utilizing reporter gene and electrophoretic mobility shift assays, we identify an 11 bp fragment of the proximal VEGF promoter as the ZNF24 binding site, essential for ZNF24-mediated repression. Moreover, we demonstrate, in two in vivo models, the potent inhibitory effect of ZNF24 on the vasculature. Expression of human ZNF24 induced in vivo vascular defects consistent with those induced by VEGF knockdown using a transgenic zebrafish model. Importantly, these defects could be rescued by VEGF overexpression. Overexpression of ZNF24 in human breast cancer cells also inhibited tumor angiogenesis in an in vivo tumor model. Analyses of human breast cancer tissues showed that ZNF24 and VEGF levels were inversely correlated in malignant compared to normal tissues. Taken together, these data demonstrate that ZNF24 represses VEGF transcription through direct binding to an 11 bp fragment of the VEGF proximal promoter and that it functions as a negative regulator of tumor growth by inhibiting angiogenesis.