2. Academic Validation
  3. The histone methyltransferase EZH2 as a druggable target in SHH medulloblastoma cancer stem cells

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

  • Oncotarget. 2017 Aug 2;8(40):68557-68570. doi: 10.18632/oncotarget.19782.
Evelina Miele # 1 2,  Sergio Valente # 3,  Vincenzo Alfano 4,  Marianna Silvano 4,  Paolo Mellini 3,  Diana Borovika 5,  Biagina Marrocco 3,  Agnese Po 6,  Zein Mersini Besharat 6,  Giuseppina Catanzaro 4,  Giuseppe Battaglia 7,  Luana Abballe 4,  Clemens Zwergel 3,  Giulia Stazi 3,  Ciro Milite 8,  Sabrina Castellano 8 9,  Marco Tafani 4,  Peteris Trapencieris 5,  Antonello Mai 3 10,  Elisabetta Ferretti 4 7
Affiliations

Affiliations

  • 1 Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Rome 00161, Italy.
  • 2 Current address: Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù, 28 Children's Hospital, IRCCS, Rome 00165, Italy.
  • 3 Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, Rome 00185, Italy.
  • 4 Department of Experimental Medicine, Sapienza University of Rome, Rome 00161, Italy.
  • 5 Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia.
  • 6 Department of Molecular Medicine, Sapienza University of Rome, Rome 00161, Italy.
  • 7 Neuromed Institute, Località Camerelle, Pozzilli 86077, Italy.
  • 8 Department of Pharmacy, University of Salerno, Fisciano 84084, Italy.
  • 9 Department of Medicine and Surgery, University of Salerno, Baronissi 84084, Italy.
  • 10 Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, Rome 00185, Italy.
  • # Contributed equally.
PMID: 28978137 DOI: 10.18632/oncotarget.19782
Abstract

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 in vitro. Finally, we generated xenograft MB-SLCs orthotopic tumors in nude mice to test MC3629 in vivo. 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.

Keywords

EZH2 inhibitors; hedgehog pathway; histone methyltransferase; medulloblastoma stem-like cells; self-renewal.

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