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Therapeutic Targeting Ewing Sarcoma through Inhibition of the FACT Complex (RNA-Seq I)

ABSTRACT: EWS/ETS fusion transcription factors, most commonly EWSR1-FLI1, drive initiation and progression of Ewing sarcoma (EwS), a highly aggressive childhood cancer of bone and soft tissues. Even though direct targeting EWSR1-FLI1 is a formidable challenge, epigenetic or transcriptional modulators have been recently proved to be promising therapeutic targets for indirectly disrupting its expression and/or function. Here, we performed transcriptome and functional genomics dataset analyses, and combined with small molecule screening of EwS lines to identify novel epigenetic/transcriptional-targeted therapeutic strategies. SSRP1 and SUPT16H, two subunits of the Facilitates Chromatin Transcription (FACT) complex, are both found to be EWSR1-FLI1-induced essential oncogenes in EwS. The FACT-targeted drug CBL0137 exhibits potent therapeutic efficacy against multiple EwS preclinical models in vitro and in vivo. Mechanistically, the FACT complex and EWS-FLI1 form oncogenic positive feedback loop via mutual transcriptional regulation and activation, and cooperatively promote cell cycle/DNA replication process and IGF1R-PI3K-AKT-mTOR pathway to drive EwS oncogenesis. The FACT inhibitor drug CBL0137 effectively targets the EWSR1-FLI1-FACT circuit, resulting in transcriptional disruption of EWS-FLI1, SSRP1 and their downstream effector oncogenic signatures. Our study illustrates a crucial role of the FACT complex in facilitating the expression and function of EWSR1-FLI1 and demonstrates FACT inhibition as a novel therapeutic strategy against EwS via indirect targeting the oncogenic fusion TF, providing preclinical support for adding EwS to CBL0137’s future clinical trials.

ORGANISM(S): Homo sapiens

PROVIDER: GSE195803 | GEO | 2022/12/31

REPOSITORIES: GEO

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Therapeutic Targeting Ewing Sarcoma through Inhibition of the FACT Complex (RNA-Seq II)

Project description:EWS/ETS fusion transcription factors, most commonly EWSR1-FLI1, drive initiation and progression of Ewing sarcoma (EwS), a highly aggressive childhood cancer of bone and soft tissues. Even though direct targeting EWSR1-FLI1 is a formidable challenge, epigenetic or transcriptional modulators have been recently proved to be promising therapeutic targets for indirectly disrupting its expression and/or function. Here, we performed transcriptome and functional genomics dataset analyses, and combined with small molecule screening of EwS lines to identify novel epigenetic/transcriptional-targeted therapeutic strategies. SSRP1 and SUPT16H, two subunits of the Facilitates Chromatin Transcription (FACT) complex, are both found to be EWSR1-FLI1-induced essential oncogenes in EwS. The FACT-targeted drug CBL0137 exhibits potent therapeutic efficacy against multiple EwS preclinical models in vitro and in vivo. Mechanistically, the FACT complex and EWS-FLI1 form oncogenic positive feedback loop via mutual transcriptional regulation and activation, and cooperatively promote cell cycle/DNA replication process and IGF1R-PI3K-AKT-mTOR pathway to drive EwS oncogenesis. The FACT inhibitor drug CBL0137 effectively targets the EWSR1-FLI1-FACT circuit, resulting in transcriptional disruption of EWS-FLI1, SSRP1 and their downstream effector oncogenic signatures. Our study illustrates a crucial role of the FACT complex in facilitating the expression and function of EWSR1-FLI1 and demonstrates FACT inhibition as a novel therapeutic strategy against EwS via indirect targeting the oncogenic fusion TF, providing preclinical support for adding EwS to CBL0137’s future clinical trials.

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Therapeutic Targeting Ewing Sarcoma through Inhibition of the FACT Complex (ChIP-Seq)

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Cancer-specific retargeting of BAF complexes by a prion-like domain [RNA-Seq]

Project description:Alterations in the function of transcriptional regulators can orchestrate oncogenic programs that are critical for the transformation and survival of cancer cells. Here we show that the BAF chromatin remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of the FET family of proteins containing prion-like domains that are frequent partners in oncogenic fusions with transcription factors. In Ewing sarcoma, characterized by the EWS-FLI1 fusion, we find that the BAF complex is recruited by EWS-FLI1 to tumor specific enhancers at GGAA microsatellite repeats and contributes to the activation of target genes. This process depends on tyrosine residues that are necessary for the aggregation properties of the EWSR1 prion-like domain and is a neomorphic feature of EWS-FLI1 compared to the wild type ETS transcription factor FLI1. Furthermore, fusion of short fragments of the EWSR1 prion-like domain to FLI1 is sufficient to recapitulate EWS-FLI1-mediated gene expression. Our studies demonstrate that the aggregation properties of prion-like domains can retarget chromatin regulatory complexes to establish and maintain oncogenic gene expression and proliferation.

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Oncofusion driven de novo enhancer assembly promotes malignancy in Ewing sarcoma via aberrant expression of the stereociliary protein LOXHD1 [enhancer knockdown]

Project description:Ewing Sarcoma (EwS) is a highly aggressive tumor of bone and soft tissues that mostly affects children and adolescents. The pathognomonic oncofusion EWSR1-ETS (EWS-FLI1/EWSR1-ERG) transcription factors drive EwS by orchestrating an oncogenic transcription program through de novo enhancers. Pharmacological targeting of these oncofusions has been challenged by unstructured prion-like domains and common DNA binding motifs in the EWSR1 and ETS protein, respectively. Alternatively, identification and characterization of mediators and downstream targets of EWS-FLI1 dependent or independent function could offer novel therapeutic options. By integrative analysis of thousands of transcriptome datasets representing pan-cancer cell lines, primary cancer, metastasis, and normal tissues, we have identified a 32 gene signature (ESS32) that could stratify EwS from pan-cancer. Of the ESS32 (Ewing Sarcoma Specific 32), LOXHD1 - coding for a stereociliary protein was the most exquisite gene expressed in EwS. CRISPR-Cas9 mediated deletion or silencing of EWS-FLI1 bound upstream de novo enhancer elements in EwS cells led to the loss of LOXHD1 expression and altered the EWS-FLI1, MYC, and HIF1 pathway genes, resulting in decreased proliferation and invasion in vitro and in vivo. These observations open up new avenues for developing LOXHD1-targeted drugs or cellular therapies for this deadly disease.

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Fusion protein EWS-FLI1 is incorporated into a protein granule in cells

Project description:Ewing sarcoma is driven by fusion proteins containing a low complexity (LC) domain that is intrinsically disordered and a powerful transcriptional regulator. The most common fusion protein found in Ewing sarcoma, EWS-FLI1, takes its LC domain from the RNA-binding protein EWSR1 (Ewing Sarcoma RNA-binding protein 1) and a DNA-binding domain from the transcription factor FLI1 (Friend Leukemia Virus Integration 1). The LC domain in EWS-FLI1 can bind RNA polymerase II (RNA Pol II) and can self-assemble through a process known as phase separation. The ability of EWSR1 and related RNA-binding proteins to assemble into ribonucleoprotein granules in cells has been intensely studied but the role of phase separation in EWS-FLI1 activity is less understood. We investigated the overlapping functions of EWSR1 and EWS-FLI1 in controlling gene expression and tumorigenic cell growth in Ewing sarcoma, and our results suggested that these proteins function closely together. We then studied the nature of interactions among EWS-FLI1, EWSR1, and RNA Pol II. We observed EWSR1 and RNA Pol II to be present in protein granules in cells. We then identified protein granules in cells associated with the fusion protein, EWS-FLI1. The tyrosine residues in the LC domain are required for the abilities of EWS-FLI1 to bind its partners, EWSR1 and RNA Pol II, and to incorporate into protein granules. These data suggest that interactions among EWS-FLI1, RNA Pol II, and EWSR1 in Ewing sarcoma can occur in the context of a molecular scaffold found within protein granules in the cell.

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USP1 expression driven by EWS-FLI1 transcription factor stabilizes Survivin and promotes Ewing sarcoma cell survival

Project description:Ewing sarcoma (EWS) is a malignant pediatric bone cancer. Most Ewing sarcomas are driven by EWS-FLI1 oncogenic transcription factor that plays roles in transcriptional regulation, DNA damage response, cell cycle checkpoint control, and alternative splicing. USP1, a deubiquitylase which regulates DNA damage and replication stress responses, is overexpressed at both the mRNA and protein levels in EWS cell lines compared to human mesenchymal stem cells, the EWS cell of origin. The functional significance of high USP1 expression in Ewing sarcoma is not known. Here, we identify USP1 as a transcriptional target of EWS-FLI1 and a key regulator of EWS cell survival. We show that EWS-FLI1 knockdown decreases USP1 mRNA and protein levels. ChIP and ChIP-seq analyses show EWS-FLI1 occupancy on the USP1 promoter. Importantly, USP1 knockdown or inhibition arrests EWS cell growth and induces cell death by apoptosis. We observe destabilization of Survivin (also known as BIRC5 or IAP4) and activation of caspases-3 and -7 following USP1 knockdown or inhibition in the absence of external DNA damage stimuli. Notably, EWS cells display hypersensitivity to combinatorial treatment of doxorubicin or etoposide, EWS standard of care drugs, and USP1 inhibitor compared to single agents alone. Together, our study demonstrates that USP1 is regulated by EWS-FLI1, the USP1-Survivin axis promotes EWS cell survival, and USP1 inhibition sensitizes EWS cells to standard of care chemotherapy.

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