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Neuropathology. 2019 Apr;39(2):71-77. doi: 10.1111/neup.12534. Epub 2019 Jan 10.

Inhibition of enhancer of zest homologue 2 is a potential therapeutic target for high-MYC medulloblastoma.

Author information

1
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2
Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan.
3
Department of Pediatrics, Oita University Faculty of Medicine, Oita, Japan.
4
Department of Pediatric Hematology-Oncology, University Hospitals Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio, USA.
5
Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, Maryland, USA.
6
Department of Neurosurgery, University Medical Center Düsseldorf, Düsseldorf, Germany.
7
Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Abstract

MYC amplification is common in Group 3 medulloblastoma and is associated with poor survival. Group 3 and Group 4 medulloblastomas are also known to have elevated levels of histone H3-lysine 27-tri-methylation (H3K27me3), at least in part due to high expression of the H3K27 methyltransferase enhancer of zest homologue 2 (EZH2), which can be regulated by MYC. We therefore examined whether MYC expression is associated with elevated EZH2 and H3K27me3 in medulloblastoma, and if high-MYC medulloblastomas are particularly sensitive to pharmacological EZH2 blockade. Western blot analysis of low (DAOY, UW228, CB SV40) and high (DAOY-MYC, UW228-MYC, CB-MYC, D425) MYC cell lines showed that higher levels of EZH2 and H3K27me3 were associated with elevated MYC. In fixed medulloblastoma samples examined using immunohistochemistry, most MYC positive tumors also had high H3K27me3, but many MYC negative ones did as well, and the correlation was not statistically significant. All high MYC lines tested were sensitive to the EZH2 inhibitor EPZ6438. Many low MYC lines also grew more slowly in the presence of EPZ6438, although DAOY-MYC cells responded more strongly than parent DAOY cultures with lower MYC levels. We find that higher MYC levels are associated with increased EZH2, and pharmacological blockade of EZH2 is a potential therapeutic strategy for aggressive medulloblastoma with elevated MYC.

KEYWORDS:

EZH2; EZH2 inhibitor; H3K27me3; MYC; medulloblastoma

PMID:
30632221
DOI:
10.1111/neup.12534
[Indexed for MEDLINE]

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