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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)3365-3382
Number of pages18
JournalNucleic Acids Research
Volume47
Issue number7
DOIs
Publication statusPublished - Jan 1 2019

ASJC Scopus subject areas

  • Genetics

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