hTERT promotes tumor angiogenesis by activating VEGF via interactions with the Sp1 transcription factor

Angiogenesis is recognized as an important hallmark of cancer. Although telomerase is thought to be involved in tumor angiogenesis, the evidence and underlying mechanism remain elusive. Here, we demonstrate that human telomerase reverse transcriptase (hTERT) activates vascular epithelial growth factor (VEGF) gene expression through interactions with the <it>VEGF</it> promoter and the transcription factor Sp1. hTERT binds to Sp1 <it>in vitro</it> and <it>in vivo</it> and stimulates angiogenesis in a manner dependent on Sp1. Deletion of the <it>mTert</it> gene in the first generation of <it>Tert</it> null mice compromised tumor growth, with reduced VEGF expression. In addition, we show that hTERT expression levels are positively correlated with those of VEGF in human gastric tumor samples. Together, our results demonstrate that hTERT facilitates tumor angiogenesis by up-regulating VEGF expression through direct interactions with the <it>VEGF</it> gene and the Sp1 transcription factor. These results provide novel insights into hTERT function in tumor progression in addition to its role in telomere maintenance.