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RING1B recruits EWSR1-FLI1 and cooperates in the remodelling of chromatin necessary for Ewing sarcoma tumorigenesis [microarray]

ABSTRACT: EWSR1-FLI1 genome reprogramming through remodeling of enhancers is determinant for Ewing sarcoma (ES) tumorigenesis. We describe a non-canonical function of RING1B, a PRC1 subunit highly expressed in primary ES tumors, co-localizing genome wide with EWSR1-FLI1 in active enhancers. While retaining its repressive canonical activity, we find RING1B as necessary for the expression of key EWSR1-FLI1 activated targets like NKX2-2, SOX2 or IGF1 where it mainly exerts a role in promoting oncogene recruitment to enhancers. Knockdown of RING1B is sufficient to impair growth of tumor xenografts and expression of EWSR1-FLI1 induced neomorphic enhancers in vivo. Restoration of RING1B ubiquitin ligase activity by the AURKB inhibitor AZD1152 decreases expression of RING1B/EWSR1-FLI1 common targets. Overall, our findings demonstrate RING1B as a critical modulator of EWSR1-FLI1 induced chromatin remodeling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133425 | GEO | 2020/10/27

REPOSITORIES: GEO

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RING1B recruits EWSR1-FLI1 and cooperates in the remodelling of chromatin necessary for Ewing sarcoma tumorigenesis [ChIP-Seq]

Project description:EWSR1-FLI1 genome reprogramming through remodeling of enhancers is determinant for Ewing sarcoma (ES) tumorigenesis. We describe a non-canonical function of RING1B, a PRC1 subunit highly expressed in primary ES tumors, co-localizing genome wide with EWSR1-FLI1 in active enhancers. While retaining its repressive canonical activity, we find RING1B as necessary for the expression of key EWSR1-FLI1 activated targets like NKX2-2, SOX2 or IGF1 where it mainly exerts a role in promoting oncogene recruitment to enhancers. Knockdown of RING1B is sufficient to impair growth of tumor xenografts and expression of EWSR1-FLI1 induced neomorphic enhancers in vivo. Restoration of RING1B ubiquitin ligase activity by the AURKB inhibitor AZD1152 decreases expression of RING1B/EWSR1-FLI1 common targets. Overall, our findings demonstrate RING1B as a critical modulator of EWSR1-FLI1 induced chromatin remodeling.

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Project description:Ewing sarcoma (ES) is an aggressive tumor molecularly defined by reciprocal translocations of EWSR1 to an ETS transcription factor. The functions of EZH2 and BMI1, two proteins of the Polycomb group (PcG) of epigenetic repressors, have been previously shown to mediate specific features in EWSR1/ETS-transformed cells. Here we have characterized the expression and function of RING1B, a PcG protein with unique abilities, in ES. RING1B is highly and universally expressed in primary ES tumors. In contrast to EZH2, RING1B expression is independent of both the oncogene and of differentiation agents. RING1B depletion affects heme biosynthesis and hematopoiesis but does not result in a widespread alteration in ES differentiation. Among the unique set of genes regulated upon RING1B depletion, FGF14 and SCN8A, interacting components of the NaV1.6 channel, are two of the most up-regulated genes. Control of FGF14 and SCN8A in ES is specific of RING1B and functionally relevant. The signaling pathway most significantly modulated by RING1B is NF-κB. Indeed, RING1B depletion results in enhanced p105/p50 expression, which specifically sensitizes ES cells to apoptosis by FGFR/SHP2/STAT3 blockade. In conclusion, we show that RING1B is pivotal in ES cells, independently of the fusion oncogene, likely reflecting essential functional traits of the cell-of-origin.

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The PRC1 protein RING1B contributes to Ewing sarcoma tumorigenesis by repressing the NaV1.6 sodium channel and modulating the NF-kB pathway, independently of the fusion oncoprotein.

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RING1B recruits EWSR1-FLI1 and cooperates in the remodeling of chromatin necessary for Ewing sarcoma tumorigenesis [RNA-seq]

Project description:RING1B recruits EWSR1-FLI1 and cooperates in the remodeling of chromatin necessary for Ewing sarcoma tumorigenesis [RNA-seq]

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