EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas
Por:
Mohammad F, Weissmann S, Leblanc B, Pandey DP, Højfeldt JW, Comet I, Zheng C, Johansen JV, Rapin N, Porse BT, Tvardovskiy A, Jensen ON, Gene-Olaciregui N, Lavarino C, Suñol M, de Torres C, Mora J, Carcaboso AM and Helin K
Publicada:
1 abr 2017
Ahead of Print:
27 feb 2017
Resumen:
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.
Filiaciones:
Mohammad F:
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark
Weissmann S:
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark
Leblanc B:
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark
The Danish Stem Cell Center (Danstem), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Pandey DP:
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark
Højfeldt JW:
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark
Comet I:
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark
Zheng C:
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark
Johansen JV:
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
Rapin N:
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
The Danish Stem Cell Center (Danstem), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
The Finsen Laboratory, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
The Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark
Porse BT:
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
The Danish Stem Cell Center (Danstem), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
The Finsen Laboratory, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Tvardovskiy A:
Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark
Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, Odense M, Denmark
Jensen ON:
Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark
Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, Odense M, Denmark
Lavarino C:
Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain
Suñol M:
Pathology, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain
de Torres C:
Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain
Mora J:
Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain
Carcaboso AM:
Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain
Helin K:
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark
The Danish Stem Cell Center (Danstem), University of Copenhagen, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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