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

Evelina Miele, Sergio Valente, Vincenzo Alfano, Marianna Silvano, Paolo Mellini, Diana Borovika, Biagina Marrocco, Agnese Po, Zein Mersini Besharat, Giuseppina Catanzaro, Giuseppe Battaglia, Luana Abballe, Clemens Zwergel, Giulia Stazi, Ciro Milite, Sabrina Castellano, Marco Tafani, Peteris Trapencieris, Antonello Mai, Elisabetta Ferretti

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)68557-68570
Number of pages14
JournalOncotarget
Volume8
Issue number40
Publication statusPublished - Sep 1 2017

Keywords

  • EZH2 inhibitors
  • Hedgehog pathway
  • Histone methyltransferase
  • Medulloblastoma stem-like cells
  • Self-renewal

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Miele, E., Valente, S., Alfano, V., Silvano, M., Mellini, P., Borovika, D., Marrocco, B., Po, A., Besharat, Z. M., Catanzaro, G., Battaglia, G., Abballe, L., Zwergel, C., Stazi, G., Milite, C., Castellano, S., Tafani, M., Trapencieris, P., Mai, A., & Ferretti, E. (2017). The histone methyltransferase EZH2 as a druggable target in SHH medulloblastoma cancer stem cells. Oncotarget, 8(40), 68557-68570.