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TRF2 positively regulates SULF2 expression increasing VEGF-A release and activity in tumor microenvironment

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Zizza, Pasquale | Dinami, Roberto | Porru, Manuela | Cingolani, Chiara | Salvati, Erica | Rizzo, Angela | d'Angelo, Carmen | Petti, Eleonora | Amoreo, Carla, Azzurra | Mottolese, Marcella | Sperduti, Isabella | Chambery, Angela | Russo, Rosita | Ostano, Paola | Chiorino, Giovanna | Blandino, Giovanni | Sacconi, Andrea | Cherfils-Vicini, Julien | Leonetti, Carlo | Gilson, Eric | Biroccio, Annamaria

Edité par CCSD ; Oxford University Press -

International audience. The telomeric protein TRF2 is overexpressed in several human malignancies and contributes to tumori-genesis even though the molecular mechanism is not completely understood. By using a high-throughput approach based on the multiplexed Luminex X-MAP technology, we demonstrated that TRF2 dramatically affects VEGF-A level in the secretome of cancer cells, promoting endothelial cell-differentiation and angio-genesis. The pro-angiogenic effect of TRF2 is independent from its role in telomere capping. Instead, TRF2 binding to a distal regulatory element promotes the expression of SULF2, an endoglucosamine-6-sulfatase that impairs the VEGF-A association to the plasma membrane by inducing post-synthetic modification of heparan sulfate proteoglycans (HSPGs). Finally, we addressed the clinical relevance of our findings showing that TRF2/SULF2 expression is a worse prognostic biomarker in colorectal cancer (CRC) patients.

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