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Selectively targeting bromodomain and extraterminal proteins for degradation as a novel anti-glioblastoma strategy [RNA-seq (time course)

ABSTRACT: Purpose: Characterization of mechanism and vulnerability of BET protein dependency in GBM cells. Methods: ChIP-seq and RNA-seq were performed on GBM cells at different time points following treatment with dBET6, a novel BET protein degrader. The transcriptome responses of parental and JQ1-resistant U87 cells to JQ1 and dBET6 were compared as well. Result: This study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins by dBET6 in GBM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE99181 | GEO | 2018/05/15

REPOSITORIES: GEO

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Project description:The pathognomonic EWS/ETS fusion transcription factors drive Ewing sarcoma (EWS) by orchestrating an oncogenic transcription program. Therapeutic targeting of EWS/ETS has not been successful; therefore identifying mediators of the EWS/ETS function could offer new therapeutic targets. Here we describe the dependency of chromatin reader BET bromodomain proteins in EWS/ETS driven transcription and investigate the potential of BET inhibitors in treating this lethal cancer. Similar to EWS/ETS fusions, knockdown of BET proteins BRD2/3/4 severely impaired the oncogenic phenotype of EWS cells. Notably, EWS/FLI1 and EWS/ERG was found to be in a transcriptional complex consisting of BRD4. RNA-Seq analysis upon BRD4 knockdown or its pharmacologic inhibition by the BET inhibitor JQ1 revealed an attenuated EWS/ETS transcriptional signature. In contrast to other reports, JQ1 reduced proliferation, and induced apoptosis through MYC-independent mechanism without affecting EWS/ETS protein levels, which was further confirmed by depleting BET proteins using PROTAC-BET degrader (BETd). Interestingly, polycomb repressive complex 2 (PRC2) associated factor PHF19 was downregulated by JQ1/BETd or BRD4 knockdown in multiple EWS cells. ChIP-seq analysis revealed occupancy of EWS/FLI1 at a distal regulatory element of PHF19 and its subsequent knockdown resulted in downregulation of PHF19 expression. Furthermore, deletion of PHF19 by CRISPR-Cas9 system lead to a decreased tumorigenic phenotype and increased sensitivity to JQ1. Importantly, PHF19 expression was associated with worse prognosis of Ewing sarcoma patients. In vivo, JQ1 demonstrated anti-tumor efficacy in multiple mouse xenograft models of EWS. Together, these results indicate that EWS/ETS require BET epigenetic reader proteins for its transcriptional program including PHF19 expression, which can be mitigated by BET inhibitors. Moreover, this study provides a clear rationale for the clinical utility of BET inhibitors in treating Ewing sarcoma.

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Selectively targeting bromodomain and extraterminal proteins for degradation as a novel anti-glioblastoma strategy [RNA-seq (time course)

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