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EZHIP boosts neuronal-like synaptic gene programs and depresses polyamine metabolism in human neural models

ABSTRACT: EZHIP (Enhancer of Zeste Inhibitory Protein) is an enigmatic protein with no discernible domains, primarily known for its role in inhibiting PRC2-mediated H3K27 methylation. It is highly expressed in posterior fossa type A (PFA) ependymoma, where it drives global chromatin reorganization. Using human neural models, we show that EZHIP activates neuronal-like transcriptional programs while repressing genes involved in metabolic regulation. Metabolomic analyses indicate that EZHIP suppresses methionine and polyamine metabolism, potentially contributing to the histone and DNA methylation alterations observed in PFA. These findings highlight a metabolic dimension to EZHIP’s function and suggest that targeting polyamine metabolism may represent a therapeutic avenue for PFA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291006 | GEO | 2025/12/04

REPOSITORIES: GEO

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

Project description: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). Here, we report that the inhibitory mechanism of this interaction 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 H3K27M peptide and binds to the SET domain of EZH2. This interaction blocks EZH2 methyltransferase activity and causes H3K27 hypomethylation, an oncogenic mechanism that may be exploited for targeted therapy in PFA ependymoma. Based on its function, we have renamed CXorf67 into EZH2 Inhibitory Protein (EZHIP).

2019-07-08 | PXD012318 | Pride

EZHIP / CXorf67 mimics oncohistones to inhibit PRC2 in PFA ependymoma

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