VEGF is a key regulator of normal and
pathologic 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. In the present study, we identify the mechanism by which ZNF24 represses
VEGF transcription. Using reporter gene and electrophoretic mobility shift assays, we identify an 11-bp fragment of the proximal
VEGF promoter as the ZNF24-binding site that is essential for ZNF24-mediated repression. We demonstrate in 2 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. 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 with normal tissues. 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.