EZHIP: a new piece of the puzzle towards understanding pediatric posterior fossa ependymoma

Abstract

Ependymomas (EPN) are tumors of the central nervous system (CNS) that can arise in the supratentorial brain (ST-EPN), hindbrain or posterior fossa (PF-EPN) or anywhere in the spinal cord (SP-EPN), both in children and adults. Molecular profiling studies have identified distinct groups and subtypes in each of these anatomical compartments. In this review, we give an overview on recent findings and new insights what is driving PFA ependymomas, which is the most common group. PFA ependymomas are characterized by a young median age at diagnosis, an overall balanced genome and a bad clinical outcome (56% 10-year overall survival). Sequencing studies revealed no fusion genes or other highly recurrently mutated genes, suggesting that the disease is epigenetically driven. Indeed, recent findings have shown that the characteristic global loss of the repressive histone 3 lysine 27 trimethylation (H3K27me3) mark in PFA ependymoma is caused by aberrant expression of the enhancer of zeste homolog inhibitory protein (EZHIP) or in rare cases by H3K27M mutations, which both inhibit EZH2 thereby preventing the polycomb repressive complex 2 (PRC2) from spreading H3K27me3. We present the current status of the ongoing work on EZHIP and its essential role in the epigenetic disturbance of PFA biology. Comparisons to the oncohistone H3K27M and its role in diffuse midline glioma (DMG) are drawn, highlighting similarities but also differences between the tumor entities and underlying mechanisms. A strong focus is to point out missing information and to present directions of further research that may result in new and improved therapies for PFA ependymoma patients.

Polycomb‐mediated gene regulation in human brain development and neurodevelopmental disorders

“…A molecular subclass of posterior fossa ependymomas (PFA ependymomas) with so far unknown cellular origin (Jenseit et al, 2022) has been reported to exhibit global reduction of H3K27me3 and hypermethylation of CpG islands (Bayliss et al, 2016), similar to the described epigenetic landscape of DIPG tumors expressing H3K27M (reviewed by Jenseit et al (2022)). Interestingly, transcriptomic analyses of PFA ependymomas revealed a subset of tumors expressing a so far uncharacterized protein encoded by the gene CXORF67 (Pajtler et al, 2018), subsequently named EZHIP (enhancer of zeste homologs inhibitory protein) (Jain et al, 2019) or CATACOMB (catalytic antagonist of Polycomb) (Piunti et al, 2019).…”

Cell-of-Origin and Genetic, Epigenetic, and Microenvironmental Factors Contribute to the Intra-Tumoral Heterogeneity of Pediatric Intracranial Ependymoma

“…A potentially druggable pathway in PFA EPN is EZHIP, although direct targeting of EZHIP might prove difficult to achieve, because no enzymatic activity has hitherto been identified [ 207 ]. High EZHIP expression sensitizes to PARP inhibitors by inhibiting homologous recombination-mediated DNA repair, especially in combination with radiotherapy, indicating this treatment approach as potentially beneficial in PFA [ 208 ].…”

“…Indeed, blockade of FGFR by dominant-negative and pharmacological inhibitors impairs cell survival and stemness features in ST-RELA cells [ 165 , 218 ] Simultaneous inhibition of CDK4/6-CCND2 (with palbociclib) and IGF2/IGF1R (with ceritinib) pathways results in combinatorial drug efficacy, highlighting that targeting distinct subpopulations may be a successful therapeutic option [ 165 ]. CDK4/6 has also been proposed as an actionable driver in PFA, because the tumor suppressor gene CDKN2A , which codes for the CDK4/6 inhibitor p16, is epigenetically silenced by H3K27 trimethylation in PFA [ 146 , 207 ]. A phase 1 trial is addressing the safety and tolerability of the CDK4/6 inhibitor ribociclib in children and young adults with recurrent brain tumors, including EPN (NCT03434262).…”

“…The PLAGL1 gene is developmentally regulated and is expressed in NSCs and developing neuroepithelial cells, with low expression in the adult brain [ 46 , 219 ]. Although the function of PLAGL1 in tumorigenesis is controversial, acting as either a tumor suppressor or an oncogene in a context-dependent manner, PLAG1L has been shown to foster progression of GBM [ 207 ]. In ST-RELA tumors, ZETA-RELA protein binds to PLAGL family TF motifs, indicating a possible corecruitment to drive ependymoma-related transcriptional programs [ 106 ].…”

“…In ST-RELA tumors, ZETA-RELA protein binds to PLAGL family TF motifs, indicating a possible corecruitment to drive ependymoma-related transcriptional programs [ 106 ]. PLAG1 is silenced during development by PRC2-mediated H3K27 trimethylation; however, in tumors with impaired PRC2 function, such as PFA and H3K27M mutant pHGG, PLAG1 is derepressed, leading to overexpression of its downstream targets, including IGF2 [ 207 ]. Therefore, it is conceivable to hypothesize that the PLAG1/PLAG1L-IGF2 axis might be therapeutically targeted in EPN.…”