Article

EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas

Nature Medicine, Springer Nature, ISSN 1546-170X

Volume 23, 4, 2017

DOI:10.1038/nm.4293, Dimensions: pub.1084129241, PMID: 28263309,

Affiliations

Organisations

  1. (1) University of Copenhagen, grid.5254.6, KU
  2. (2) The Finsen Laboratory, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  3. (3) University of Southern Denmark, grid.10825.3e, SDU
  4. (4) Hospital Sant Joan de Déu Barcelona, grid.411160.3

Countries

Spain

Denmark

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Europe

Description

Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain tumor that is located in the pons and primarily affects children. Nearly 80% of DIPGs harbor mutations in histone H3 genes, wherein lysine 27 is substituted with methionine (H3K27M). H3K27M has been shown to inhibit polycomb repressive complex 2 (PRC2), a multiprotein complex responsible for the methylation of H3 at lysine 27 (H3K27me), by binding to its catalytic subunit EZH2. Although DIPGs with the H3K27M mutation show global loss of H3K27me3, several genes retain H3K27me3. Here we describe a mouse model of DIPG in which H3K27M potentiates tumorigenesis. Using this model and primary patient-derived DIPG cell lines, we show that H3K27M-expressing tumors require PRC2 for proliferation. Furthermore, we demonstrate that small-molecule EZH2 inhibitors abolish tumor cell growth through a mechanism that is dependent on the induction of the tumor-suppressor protein p16INK4A. Genome-wide enrichment analyses show that the genes that retain H3K27me3 in H3K27M cells are strong polycomb targets. Furthermore, we find a highly significant overlap between genes that retain H3K27me3 in the DIPG mouse model and in human primary DIPGs expressing H3K27M. Taken together, these results show that residual PRC2 activity is required for the proliferation of H3K27M-expressing DIPGs, and that inhibition of EZH2 is a potential therapeutic strategy for the treatment of these tumors.

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University of Copenhagen

University of Southern Denmark

Danish Open Access Indicator

2017: Unused

Research area: Medicine

Danish Bibliometrics Indicator

2017: Level 2

Research area: Medicine

Dimensions Citation Indicators

Times Cited: 175

Field Citation Ratio (FCR): 54.81

Relative Citation ratio (RCR): 9.49