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@ARTICLE{Hbner:143291,
      author       = {J.-M. Hübner$^*$ and T. Müller$^*$ and D. N.
                      Papageorgiou$^*$ and M. Mauermann$^*$ and J. Krijgsveld$^*$
                      and R. B. Russell and D. W. Ellison and S. Pfister$^*$ and
                      K. Pajtler$^*$ and M. Kool$^*$},
      title        = {{EZHIP} / {CX}orf67 mimics {K}27{M} mutated oncohistones
                      and functions as an intrinsic inhibitor of {PRC}2 function
                      in aggressive posterior fossa ependymoma.},
      journal      = {Neuro-Oncology},
      volume       = {21},
      number       = {7},
      issn         = {1523-5866},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DKFZ-2019-00889},
      pages        = {878-889},
      year         = {2019},
      abstract     = {Posterior fossa A (PFA) ependymomas comprise one out of
                      nine 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 CXorf67 overexpression as hallmark of
                      PFA ependymoma and showed that CXorf67 can interact with
                      EZH2 thereby inhibiting polycomb repressive complex 2
                      (PRC2), but the mechanism of action remained unclear.We
                      performed mass spectrometry (MS) and peptide modelling
                      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.We find that the inhibitory
                      mechanism of CXorf67 is similar as in 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 of EZH2. This interaction blocks
                      EZH2 methyltransferase activity and inhibits PRC2 function
                      causing de-repression of PRC2 target genes including genes
                      involved in neurodevelopment.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 into EZH Inhibitory Protein (EZHIP).},
      cin          = {B062 / B230},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)B230-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30923826},
      doi          = {10.1093/neuonc/noz058},
      url          = {https://inrepo02.dkfz.de/record/143291},
}