New pathways linking telomeres to cancer
Il 18/10/2019 ore 12.00 - 13.00
Sala Conferenze Cnr, Area della Ricerca Na1, via Pietro Castellino 111, 80131 Napoli
Dr. Pasquale Zizza (Oncogenomic and Epigenetic Unit, IRCCS, Regina Elena National Cancer Institute, Roma, Italy) will give a seminar on “New pathways linking telomeres to cancer”.
Telomere maintenance is thought to be necessary for indefinite cancer cell growth. To maintain telomere length, 80-90% of human tumors reactivate the enzyme telomerase, while the remaining 10-20% activate an alternative mechanism based on homologous recombination (ALT). These findings led to development of telomerase-based therapeutic strategies for cancer treatment. Unfortunately, clinical trials with telomerase inhibitors have shown limited benefits, probably due to the heterogenicity of the telomere length within the tumors. This is why our research group focused in studying the oncogenic role of other telomere components.
Data in the literature evidenced that the telomeric protein TRF2 is overexpressed in various human malignancies and in the vasculature of many cancer types, it is regulated by the Wnt/?-catenin/WT1/p53 pathways and correlates with tumor grade. Interestingly, our studies evidenced that tumorigenic potential of TRF2 does not exclusively depend on telomere protection. Indeed, combining chromatin immunoprecipitation with high-throughput DNA sequencing (ChIP-Seq), TRF2 has been found to affect gene expression through its binding to telomere-like interstitial sequences (ITS) distributed into the human genome. Despite this, many unknowns remain concerning the consequence of TRF2 modulation in human cancers and therefore its use in innovative cancer therapies.
Notably, our work aims at investigating the mechanisms through which TRF2 affects tumor formation and progression. In detail, we first revealed that TRF2 promotes tumorigenesis through the positive regulation of a gene, HS3ST4, encoding for a sulfotranferase involved in post-synthetic modification of certain Heparan Sulfate Proteoglycans (HSPG). More recently, our findings paved the way to the new concept that TRF2 is a master regulator of glycocalyx structure in cancer cells. In particular, we found that TRF2 affects the expression of a network of glycocalyx-related genes (GPC6, VCAN and SULF2) that, controlling NK cell recruitment/activation and VEGF-A secretion, impact on tumor formation and progression. Altogether, our studies reveal how changes in TRF2 expression are translated into oncogenic events linked to cancer formation and progression, identifying a multi-hit telomeric target for innovative anti-cancer therapies.
Organizzato da:
Cnr - Istituto di Biochimica e Biologia Cellulare
Referente organizzativo:
Alessia Varone
Cnr - Istituto di Biochimica e Biologia Cellulare
a.varone@ibp.cnr.it
081 6132495
Modalità di accesso: ingresso libero
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