Project description:A subgroup of Posterior fossa ependymomas show reduced H3K27me3, global DNA hypomethylation, are more invasive, exhibit poor prognosis and epigenetically deregulated genes converge on radial glial factors, suggesting developing cerebellar radial glia as candidate cells-of-origin.
Project description:A subgroup of Posterior fossa ependymomas show reduced H3K27me3, global DNA hypomethylation, are more invasive, exhibit poor prognosis and epigenetically deregulated genes converge on radial glial factors, suggesting developing cerebellar radial glia as candidate cells-of-origin.
Project description:A subset of genomically silent childhood posterior fossa ependymomas show reduced H3K27me3, global DNA hypomethylation, are more invasive, exhibit poor prognosis and epigenetically deregulated genes converge on radial glial factors, suggesting developing cerebellar radial glia as candidate cells-of-origin.
Project description:A subgroup of Posterior fossa ependymomas show reduced H3K27me3 are more invasive, exhibit poor prognosis and epigenetically deregulated genes converge on radial glial factors, suggesting developing cerebellar radial glia as candidate cells-of-origin.
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).
Project description:Childhood Posterior Fossa-A ependymomas (PFAs) have limited treatment options. Integrated metabolic/epigenetic analyses performed to discover therapeutic targets in PFAs demonstrated enhanced glycolysis and TCA-cycle metabolism. PFAs exhibit low H3K27me3, as in H3K27M gliomas. Therefore, we subjected them to panobinostat which kills H3K27M cells, along with the metabolic inhibitor metformin. Combined treatment increased H3K27me3, suppressed metabolism and demonstrated potent therapeutic efficacy in vitro and in vivo, suggesting promising therapeutic strategies.