The transcription factor E2F1 and the SR protein SC35 control the ratio of pro-angiogenic versus antiangiogenic isoforms of vascular endothelial growth factor-A to inhibit neovascularization in vivo

摘要

The transcription factor E2F1 has a crucial role in the control of cell growth and has been shown to regulate neoangiogenesis in a p53-dependent manner through inhibition of activity of the VEGF-A (vascular endothelial growth factor) promoter. Besides being regulated by transcription, VEGF-A is also highly regulated by pre-mRNA alternative splicing, resulting in the expression of several VEGF isoforms with either pro-(VEGFxxx) or anti-(VEGFxxxb) angiogenic properties. Recently, we identified the SR (Ser-Rich/Arg) protein SC35, a splicing factor, as a new transcriptional target of E2F1. Here, we show that E2F1 downregulates the activity of the VEGF-A promoter in tumour cells independently of p53, leading to a strong decrease in VEGFxxx mRNA levels. We further show that, strikingly, E2F1 alters the ratio of pro-VEGFxxx versus anti-VEGFxxxb angiogenic isoforms, favouring the antiangiogenic isoforms, by a mechanism involving the induction of SC35 expression. Finally, using lung tumour xenografts in nude mice, we provide evidence that E2F1 and SC35 proteins increase the VEGF165b/VEGF ratio and decrease tumour neovascularization in vivo. Overall, these findings highlight E2F1 and SC35 as two regulators of the VEGFxxx/VEGFxxxb angiogenic switch in human cancer cells, a role that could be crucial during tumour progression, as well as in tumour response to antiangiogenic therapies.