{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n EZHIP (formerly known as CXorf67) has emerged as a critical regulator of chromatin structure and gene expression by modulating the activity of the Polycomb Repressive Complex 2 (PRC2). In several tumors—notably posterior fossa type A ependymomas—elevated EZHIP expression correlates with a global reduction in the repressive H3K27 trimethylation (H3K27me3) mark. Mechanistic studies have demonstrated that EZHIP directly binds to core PRC2 components (EZH2, SUZ12, and EED) and, through a highly conserved C‐terminal peptide that mimics the H3K27M oncohistone, occupies the active site of EZH2 to inhibit its catalytic activity; this results in impaired deposition of H3K27me3 over broad chromatin domains while allowing focal retention at CpG islands."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " In addition to this epigenetic deregulation function, EZHIP has been implicated in the suppression of homologous recombination (HR)-mediated DNA repair by interacting with PALB2, thereby perturbing the PALB2–BRCA2 interaction; this defect in HR repair contributes to tumor cell sensitivity to poly(ADP-ribose) polymerase inhibitors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Beyond its oncogenic role, EZHIP is also expressed in normal tissues such as the gonads, where it serves a physiological function by attenuating PRC2 activity during gametogenesis—limiting H3K27 di- and trimethylation and thereby influencing follicle maintenance and fertility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Collectively, these findings highlight the dual nature of EZHIP as both an oncogenic driver through PRC2 inhibition and a normal developmental regulator of the epigenetic landscape, opening avenues for targeted therapy in tumors characterized by its overexpression.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kristian W Pajtler, Ji Wen, Martin Sill, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Neuropathol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00401-018-1877-0"}], "href": "https://doi.org/10.1007/s00401-018-1877-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29909548"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29909548"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Siddhant U Jain, Truman J Do, Peder J Lund, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-019-09981-6"}], "href": "https://doi.org/10.1038/s41467-019-09981-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31086175"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31086175"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jens-Martin Hübner, Torsten Müller, Dimitris N Papageorgiou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuro Oncol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/neuonc/noz058"}], "href": "https://doi.org/10.1093/neuonc/noz058"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30923826"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30923826"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Siddhant U Jain, Andrew Q Rashoff, Samuel D Krabbenhoft, et al. "}, {"type": "b", "children": [{"type": "t", "text": "H3 K27M and EZHIP Impede H3K27-Methylation Spreading by Inhibiting Allosterically Stimulated PRC2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2020.09.028"}], "href": "https://doi.org/10.1016/j.molcel.2020.09.028"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33049227"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33049227"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Aruna Nambirajan, Agrima Sharma, Madhu Rajeshwari, et al. "}, {"type": "b", "children": [{"type": "t", "text": "EZH2 inhibitory protein (EZHIP/Cxorf67) expression correlates strongly with H3K27me3 loss in posterior fossa ependymomas and is mutually exclusive with H3K27M mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain Tumor Pathol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10014-020-00385-9"}], "href": "https://doi.org/10.1007/s10014-020-00385-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33130928"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33130928"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Andrea Piunti, Edwin R Smith, Marc A J Morgan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CATACOMB: An endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Adv (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/sciadv.aax2887"}], "href": "https://doi.org/10.1126/sciadv.aax2887"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31281901"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31281901"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Roberta Ragazzini, Raquel Pérez-Palacios, Irem H Baymaz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-019-11800-x"}], "href": "https://doi.org/10.1038/s41467-019-11800-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31451685"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31451685"}]}]}]}