TRF2 positively regulates SULF2 expression increasing VEGF-A release and activity in tumor microenvironment. Issue 7 (30th January 2019)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Nucleic acids research. Volume 47:Issue 7(2019)
• Page Start: 3365
• Page End: 3382
• Publication Date: 2019-01-30
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkz041
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: The telomeric protein TRF2 is overexpressed in several human malignancies and contributes to tumorigenesis 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 angiogenesis. 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.