| Literature DB >> 26626085 |
Marco Gallo1, Fiona J Coutinho2, Robert J Vanner2, Tenzin Gayden3, Stephen C Mack4, Alex Murison5, Marc Remke1, Ren Li6, Naoya Takayama5, Kinjal Desai7, Lilian Lee1, Xiaoyang Lan2, Nicole I Park2, Dalia Barsyte-Lovejoy8, David Smil8, Dominik Sturm9, Michelle M Kushida1, Renee Head1, Michael D Cusimano10, Mark Bernstein11, Ian D Clarke1, John E Dick5, Stefan M Pfister9, Jeremy N Rich12, Cheryl H Arrowsmith8, Michael D Taylor13, Nada Jabado3, David P Bazett-Jones6, Mathieu Lupien14, Peter B Dirks15.
Abstract
Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM.Entities:
Mesh：
Substances：
Year: 2015 PMID： 26626085 DOI： 10.1016/j.ccell.2015.10.005
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743