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C11orf95-RELA fusion drives aberrant gene expression through the unique epigenetic regulation for ependymoma formation.

ABSTRACT: Recurrent C11orf95-RELA fusions (RELA^FUS) are the hallmark of supratentorial ependymomas. The presence of RELA as the fusion partner indicates a close association of aberrant NF-κB activity with tumorigenesis. However, the oncogenic role of the C11orf95 has not been determined. Here, we performed ChIP-seq analyses to explore genomic regions bound by RELA^FUS and H3K27ac proteins in human 293T and mouse ependymoma cells. We then utilized published RNA-Seq data from human and mouse RELA^FUS tumors and identified target genes that were directly regulated by RELA^FUS in these tumors. Subsequent transcription factor motif analyses of RELA^FUS target genes detected a unique GC-rich motif recognized by the C11orf95 moiety, that is present in approximately half of RELA^FUS target genes. Luciferase assays confirmed that a promoter carrying this motif is sufficient to drive RELA^FUS-dependent gene expression. Further, the RELA^FUS target genes were found to be overlapped with Rela target genes primarily via non-canonical NF-κB binding sites. Using a series of truncation and substitution mutants of RELA^FUS, we also show that the activation domain in the RELA^FUS moiety is necessary for the regulation of gene expression of these RELA^FUS target genes. Lastly, we performed an anti-cancer drug screening with mouse ependymoma cells and identified potential anti-ependymoma drugs that are related to the oncogenic mechanism of RELA^FUS. These findings suggested that RELA^FUS might induce ependymoma formation through oncogenic pathways orchestrated by both C11orf95 and RELA target genes. Thus, our study unveils a complex gene function of RELA^FUS as an oncogenic transcription factor in RELA^FUS positive ependymomas.

SUBMITTER: Ozawa T

PROVIDER: S-EPMC7941712 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Extensive molecular analyses of ependymal tumors have revealed that supratentorial and posterior fossa ependymomas have distinct molecular profiles and are likely to be different diseases. The presence of C11orf95-RELA fusion genes in a subset of supratentorial ependymomas (ST-EPN) indicated the existence of molecular subgroups. However, the pathogenesis of RELA fusion-negative ependymomas remains elusive. To investigate the molecular pathogenesis of these tumors and validate the molecular classification of ependymal tumors, we conducted thorough molecular analyses of 113 locally diagnosed ependymal tumors from 107 patients in the Japan Pediatric Molecular Neuro-Oncology Group. All tumors were histopathologically reviewed and 12 tumors were re-classified as non-ependymomas. A combination of RT-PCR, FISH, and RNA sequencing identified RELA fusion in 19 of 29 histologically verified ST-EPN cases, whereas another case was diagnosed as ependymoma RELA fusion-positive via the methylation classifier (68.9%). Among the 9 RELA fusion-negative ST-EPN cases, either the YAP1 fusion, BCOR tandem duplication, EP300-BCORL1 fusion, or FOXO1-STK24 fusion was detected in single cases. Methylation classification did not identify a consistent molecular class within this group. Genome-wide methylation profiling successfully sub-classified posterior fossa ependymoma (PF-EPN) into PF-EPN-A (PFA) and PF-EPN-B (PFB). A multivariate analysis using Cox regression confirmed that PFA was the sole molecular marker which was independently associated with patient survival. A clinically applicable pyrosequencing assay was developed to determine the PFB subgroup with 100% specificity using the methylation status of 3 genes, CRIP1, DRD4 and LBX2. Our results emphasized the significance of molecular classification in the diagnosis of ependymomas. RELA fusion-negative ST-EPN appear to be a heterogeneous group of tumors that do not fall into any of the existing molecular subgroups and are unlikely to form a single category.

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C11orf95-RELA fusion drives aberrant gene expression through the unique epigenetic regulation for ependymoma formation.

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