Neuro-Oncology

, volume 21 , issue 7 , pages 878-889

EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma

Jens Martin Hübner ^{1, 2, 3}

Torsten Müller ^{4, 5}

Dimitris N Papageorgiou ¹

Monika Mauermann ^{1, 2}

J. Krijgsveld ^{4, 5}

Robert B. Russell ^{6, 7}

David W. Ellison ⁸

Stefan M. Pfister ^{1, 2, 9}

Kristian W. Pajtler ^{1, 2, 9}

M Kool ^{1, 2}

Hide authors affiliations Show authors affiliations: 9 affiliations

Division of Pediatric Neurooncology, German Cancer Consortium, German Cancer Research Center (DKFZ), Heidelberg, Germany |

Hopp Children’s Cancer Center, Heidelberg, Germany |

Faculty of Biosciences, Heidelberg University, Heidelberg, Germany |

⁴

Division of Proteomics of Stem Cells and Cancer, DKFZ, Heidelberg, Germany |

⁵

Medical Faculty, Heidelberg University, Heidelberg, Germany |

⁶

Heidelberg University Biochemistry Center, Heidelberg, Germany |

⁷

BioQuant, Heidelberg University, Heidelberg, Germany |

⁸

Department of Pathology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA |

⁹

Department of Pediatric Oncology, Hematology and Immunology, University Hospital, Heidelberg, Germany |

Publication type: Journal Article

Publication date: 2019-04-29

Oxford University Press

Neuro-Oncology

scimago Q1

wos Q1

SJR: 6.974

CiteScore: 30.2

Impact factor: 13.4

ISSN: 15228517, 15235866

DOI: 10.1093/neuonc/noz058

Copy DOI

PubMed ID: 30923826

Cancer Research

Oncology

Neurology (clinical)

Abstract

Background

Posterior fossa A (PFA) ependymomas are one of 9 molecular groups of ependymoma. PFA tumors are mainly diagnosed in infants and young children, show a poor prognosis, and are characterized by a lack of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark. Recently, we reported overexpression of chromosome X open reading frame 67 (CXorf67) as a hallmark of PFA ependymoma and showed that CXorf67 can interact with enhancer of zeste homolog 2 (EZH2), thereby inhibiting polycomb repressive complex 2 (PRC2), but the mechanism of action remained unclear.

Methods

We performed mass spectrometry and peptide modeling analyses to identify the functional domain of CXorf67 responsible for binding and inhibition of EZH2. Our findings were validated by immunocytochemistry, western blot, and methyltransferase assays.

Results

We find that the inhibitory mechanism of CXorf67 is similar to diffuse midline gliomas harboring H3K27M mutations. A small, highly conserved peptide sequence located in the C-terminal region of CXorf67 mimics the sequence of K27M mutated histones and binds to the SET domain (Su(var)3-9/enhancer-of-zeste/trithorax) of EZH2. This interaction blocks EZH2 methyltransferase activity and inhibits PRC2 function, causing de-repression of PRC2 target genes, including genes involved in neurodevelopment.

Conclusions

Expression of CXorf67 is an oncogenic mechanism that drives H3K27 hypomethylation in PFA tumors by mimicking K27M mutated histones. Disrupting the interaction between CXorf67 and EZH2 may serve as a novel targeted therapy for PFA tumors but also for other tumors that overexpress CXorf67. Based on its function, we have renamed CXorf67 as “EZH Inhibitory Protein” (EZHIP).

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Cite this

GOST |

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GOST Copy

Hübner J. M. et al. EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma // Neuro-Oncology. 2019. Vol. 21. No. 7. pp. 878-889.

GOST all authors (up to 50) Copy

Hübner J. M., Müller T., Papageorgiou D. N., Mauermann M., Krijgsveld J., Russell R., Ellison D. W., Pfister S. M., Pajtler K. W., Kool M. EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma // Neuro-Oncology. 2019. Vol. 21. No. 7. pp. 878-889.

RIS |

Cite this

RIS Copy

TY - JOUR

DO - 10.1093/neuonc/noz058

UR - https://doi.org/10.1093/neuonc/noz058

TI - EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma

T2 - Neuro-Oncology

AU - Hübner, Jens Martin

AU - Müller, Torsten

AU - Papageorgiou, Dimitris N

AU - Mauermann, Monika

AU - Krijgsveld, J.

AU - Russell, Robert B.

AU - Ellison, David W.

AU - Pfister, Stefan M.

AU - Pajtler, Kristian W.

AU - Kool, M

PY - 2019

DA - 2019/04/29

PB - Oxford University Press

SP - 878-889

IS - 7

VL - 21

PMID - 30923826

SN - 1522-8517

SN - 1523-5866

ER -

BibTex |

Cite this

BibTex (up to 50 authors) Copy

@article{2019_Hübner,

author = {Jens Martin Hübner and Torsten Müller and Dimitris N Papageorgiou and Monika Mauermann and J. Krijgsveld and Robert B. Russell and David W. Ellison and Stefan M. Pfister and Kristian W. Pajtler and M Kool},

title = {EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma},

journal = {Neuro-Oncology},

year = {2019},

volume = {21},

publisher = {Oxford University Press},

month = {apr},

url = {https://doi.org/10.1093/neuonc/noz058},

number = {7},

pages = {878--889},

doi = {10.1093/neuonc/noz058}

}

MLA

Cite this

MLA Copy

Hübner, Jens Martin, et al. “EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma.” Neuro-Oncology, vol. 21, no. 7, Apr. 2019, pp. 878-889. https://doi.org/10.1093/neuonc/noz058.

Publisher

Oxford University Press

Journal

Neuro-Oncology

scimago Q1

wos Q1

SJR

6.974

CiteScore

30.2

Impact factor

13.4

ISSN

15228517 (Print)

15235866 (Electronic)