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• W2336619227 abstract "Fusion-positive alveolar rhabdomyosarcoma (FP-RMS) is a paediatric tumour driven by an oncogenic fusion transcription factor, PAX3-FOXO1. Conventional chemotherapy is only effective for low risk patients which carry no metastasis, achieving a 5-year overall survival of 65%. The unique presence of this fusion protein in FP-RMS as well as the tumour cell survival dependency on PAX3-FOXO1 make this transcription factor a promising target for therapy. However, due to the difficulties associated with drug development targeting transcription factors, we performed a combined proteomic and genetic screen to identify new druggable co-regulators of PAX3-FOXO1 transcriptional activity. Interactor candidates were defined by mass spectrometry analysis of proteins co-purified with the fusion protein and individually validated for their relevance for PAX3-FOXO1 activity through siRNA silencing. The chromodomain-DNA-binding protein 4 (CHD4), a nucleosome remodeler and core member of the NuRD complex (Nucleosome Remodelling and Deacetylase), was identified as an essential positive co-regulator of PAX3-FOXO1 transcriptional activity. ChIP-qPCR experiments demonstrated that CHD4 not only co-localizes with PAX3-FOXO1 in the FP-RMS genome but also it is necessary for the binding of the fusion protein to cis-regulatory sites for a subset of its target genes. Consequently, CHD4 silencing affected the expression of more than 50% of PAX3-FOXO1 regulated target genes. Additionally, depletion of CHD4 impaired FP-RMS cell proliferation and caused a complete regression of xenograft tumours in mice. Moreover, CHD4 silencing had no effect in cell proliferation of human myoblasts or fibroblasts, suggesting a unique tumour dependency on this chromatin remodeler. In summary, our data propose that CHD4 has a crucial role as a co-regulator of PAX3-FOXO1 driven gene expression whose presence is required for FP-RMS cell viability. To our knowledge, CHD4 is the first identified chromatin remodeler associated with PAX3-FOXO1 transcriptional activity, thus highlighting the relevance of epigenetic regulation in FP-RMS tumour development. Collectively, our findings suggest CHD4 as a potential novel therapeutic target in this childhood malignancy, and are motivating ongoing work aimed at finding first-in-class small molecules to inhibit CHD4. This abstract is also presented as Poster A20. Citation Format: Joana Marques, Maria Boehm, Marco Wachtel, Beat Schaefer. The chromatin remodeler CHD4 as a potential specific target for alveolar rhabdomyosarcoma therapy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr PR10." @default.
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• W2336619227 date "2016-03-01" @default.
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• W2336619227 title "Abstract PR10: The chromatin remodeler CHD4 as a potential specific target for alveolar rhabdomyosarcoma therapy" @default.
• W2336619227 doi "https://doi.org/10.1158/1538-7445.pedca15-pr10" @default.
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