The histone methyltransferase EZH2 as a druggable target in SHH medulloblastoma cancer stem cells

• Published in: Oncotarget 2017-09, Vol.8 (40), p.68557-68570
• Main Authors: Miele, Evelina, Valente, Sergio, Alfano, Vincenzo, Silvano, Marianna, Mellini, Paolo, Borovika, Diana, Marrocco, Biagina, Po, Agnese, Besharat, Zein Mersini, Catanzaro, Giuseppina, Battaglia, Giuseppe, Abballe, Luana, Zwergel, Clemens, Stazi, Giulia, Milite, Ciro, Castellano, Sabrina, Tafani, Marco, Trapencieris, Peteris, Mai, Antonello, Ferretti, Elisabetta
• Format: Article
• Language: English
• Subjects: Research Paper
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.19782

The histone methyltransferase EZH2 plays a role in maintenance of the stem component of cancer, and its overexpression and/or mutation typically drives tumor aggressiveness, drug resistance and patients' poor prognosis. In this study, we use mouse and human medulloblastoma stem-like cells belonging to the Sonic Hedgehog subgroup (SHH MB-SLCs) and demonstrate that genetic suppression of EZH2 reduces the level of its histone mark H3K27me3 and lowers proliferation and self-renewal. We designed an EZH2 inhibitor (EZH2i) as a simplified analog of EPZ005687 and GSK2816126, MC3629, and we tested its biological activity in SHH MB-SLCs. Pharmacological inhibition of EZH2 impairs SHH MB cells proliferation and self-renewal, and induces apoptosis . Finally, we generated xenograft MB-SLCs orthotopic tumors in nude mice to test MC3629 . In treated mice, we observed impairment of tumor growth, together with induction of apoptosis and reduction of proliferation and stemness. Overall, these findings describe EZH2 as a druggable target in MB and provide insight into the biological activity of MC3629 as an EZH2i.