Open AccessThe histone methyltransferase EZH2 as a druggable target in SHH medulloblastoma cancer stem cells
Author(s) -
Evelina Miele,
Sérgio Valente,
Vincenzo Alfano,
Marianna Silvano,
Paolo Mellini,
Diana Borovika,
Biagina Marrocco,
Agnese Pò,
Zein Mersini Besharat,
Giuseppina Catanzaro,
Giuseppe Battaglia,
Luana Abballe,
Clemens Zwergel,
Giulia Stazi,
Ciro Milite,
Sabrina Castellano,
Marco Tafani,
Pēteris Trapencieris,
Antonello Mai,
Elisabetta Ferretti
Publication year - 2017
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.19782
Subject(s) - ezh2 , medulloblastoma , cancer research , sonic hedgehog , stem cell , histone methyltransferase , cancer stem cell , biology , methyltransferase , hedgehog signaling pathway , medicine , epigenetics , microbiology and biotechnology , signal transduction , methylation , genetics , gene
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.