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LIN28B underlies the pathogenesis of a subclass of Ewing sarcoma

ABSTRACT: Ewing sarcoma (EwS) is associated with poor prognosis despite current multimodal therapy. Targeting of EWS-FLI-1, the fusion protein responsible for its pathogenesis, and its principal downstream targets has not yet produced satisfactory therapeutic options, fuelling the search for alternative approaches. Here, we show that the oncofoetal RNA-binding protein Lin28B regulates the stability of EWS-FLI-1 mRNA in about 10% of EwS. Lin28B depletion in these tumours leads to a decrease in expression of EWS-FLI-1 and its direct transcriptional network, abrogating EwS cell self-renewal and tumorigenicity. Moreover, pharmacological inhibition of Lin28B mimics the effect of Lin28B depletion, suggesting that Lin28B sustains the emergence of a subset of EwS in which it also serves as an effective therapeutic target.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE137703 | GEO | 2020/04/30

REPOSITORIES: GEO

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LIN28B underlies the pathogenesis and therapeutic sensitivity of a subclass of Ewing sarcoma

Project description:Ewing sarcoma (EwS) is a pediatric bone malignancy associated with high mortality despite aggressive multimodal therapy. Targeting EWS-FLI-1, the fusion protein responsible for EwS pathogenesis, or its principal downstream target gene products have not produced effective therapeutic options, fuelling the quest for alternative approaches. Here, we show that the oncofoetal RNA-binding protein Lin28B is expressed in a subset of EwS in which it directly binds and safeguards EWS-FLI-1 transcripts. Depletion and pharmacologic inhibition of Lin28B in primary patient-derived EwS cultures led not only to a decrease in EWS-FLI-1 expression but also to the deconstruction of its direct transcriptional network, abrogating EwS cell self-renewal and tumorigenicity. Our observations demonstrate that Lin28B provides indispensable support for EWS-FLI-1 to sustain the emergence of a EwS subset in which it also constitutes a promising therapeutic target.

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Tumor-specific retargeting of an oncogenic transcription factor chimera results in dysregulation of chromatin and transcription

Project description:Using EWS-FLI and its parental transcription factor, FLI1, we created a unique experimental system to address questions regarding the genomic mechanisms by which chimeric transcription factors cause cancer. We found that in tumor cells, EWS-FLI targets regions of the genome distinct from FLI1, despite identical DNA-binding domains. In primary endothelial cells, however, EWS-FLI and FLI1 demonstrate similar targeting. To understand this mistargeting, we examined chromatin organization. Regions targeted by EWS-FLI are normally repressed and nucleosomal in primary endothelial cells. In tumor cells, however, bound regions are nucleosome-depleted and harbor the chromatin signature of enhancers. We next demonstrated that through chimerism, EWS-FLI acquired the ability to alter chromatin. Expression of EWS-FLI results in nucleosome depletion at targeted sites, whereas silencing of EWS-FLI in tumor cells restored nucleosome occupancy. Thus, the EWS-FLI chimera acquired chromatin-altering activity, leading to mistargeting, chromatin disruption, and ultimately transcriptional dysregulation. Examination of two transcription factors in two different cell types, as well as three histone methylation marks and FAIRE

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Tumor-specific retargeting of an oncogenic transcription factor chimera results in dysregulation of chromatin and transcription

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EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma (4C)

Project description:Ewing sarcoma is a prototypical fusion transcription factor-associated pediatric cancer that expresses EWS/FLI or highly related fusions. EWS/FLI dysregulates transcription to induce and maintain sarcomagenesis, but the mechanisms utilized are not fully understood. We therefore sought to define the global effects of EWS/FLI on chromatin conformation and transcription in Ewing sarcoma. We found that EWS/FLI (and EWS/ERG) genomic localization is largely conserved across multiple patient-derived Ewing sarcoma cell lines. EWS/FLI binding is primarily associated with compartment activation, establishment of topologically-associated domain (TAD) boundaries, enhancer-promoter looping that involve both intra- and inter-TAD interactions, and gene activation. Importantly, local chromatin features provide the basis for transcriptional heterogeneity in regulation of direct EWS/FLI target genes across different Ewing sarcoma cell lines. These data demonstrate a key role of EWS/FLI in mediating genome-wide changes in chromatin configuration and support the notion that fusion transcription factors serve as master regulators through three-dimensional reprogramming of chromatin.

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EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma (RNA-Seq)

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EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma (CUT&Tag II)

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EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma (CuT&Tag I)

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EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma (Hi-C)

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A novel role for the EWS portion of EWS/FLI in binding GGAA-microsatellites required for oncogenic transformation in Ewing sarcoma [RNA-Seq]

Project description:Ewing sarcoma usually expresses the EWS/FLI fusion transcription factor oncoprotein. EWS/FLI regulates myriad genes required for Ewing sarcoma development. EWS/FLI binds GGAA-microsatellite sequences in vivo and in vitro, and these sequences provide EWS/FLI-mediated activation to reporter constructs, suggesting that they function as EWS/FLI-response elements. Genomic GGAA-microsatellites are highly variable and polymorphic. Current data suggest that there is an optimal “sweet-spot” GGAA-microsatellite length (of 18-26 GGAA repeats) that confers maximal EWS/FLI-responsiveness to target genes, but the mechanistic basis for this was not known. We now demonstrate the absolute necessity of an EWS/FLI-bound GGAA-microsatellite in regulation of the NR0B1 gene, as well as for Ewing sarcoma proliferation and oncogenic transformation. Biochemical studies, using recombinant Δ22 (a version of EWS/FLI containing only the FLI portion) demonstrated a stoichiometry of one Δ22-monomer binding to every two consecutive GGAA-repeats on shorter GGAA-microsatellite sequences. Surprisingly, the affinity for Δ22 binding to GGAA-microsatellites significantly decreased, and ultimately became unmeasureable, when the size of the GGAA-microsatellite was increased to the “sweet-spot” length. In contrast, a fully-functional EWS/FLI mutant (Mut9) that retains approximately half of the EWS portion of the fusion showed low affinity for smaller GGAA-microsatellites, but instead significantly increased its affinity at “sweet-spot” microsatellite lengths. Single-gene ChIP and genome-wide ChIP-seq and RNA-seq studies extended these findings to the in vivo setting. Taken together, these data demonstrate the absolute requirement of GGAA-microsatellites as EWS/FLI activating response elements in vivo and reveal an unsuspected novel role for the EWS portion of the EWS/FLI fusion in binding to optimal-length GGAA-microsatellites.

2017-10-22 | GSE94502 | GEO

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