Abstract PR10: The chromatin remodeler CHD4 as a potential specific target for alveolar rhabdomyosarcoma therapy

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 im...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Epigenetics Source Type: research