Abstract A02: The epigenetic modifier CHAF1A opposes neuroblastoma differentiation via metabolic reprogramming

• Published in: Molecular cancer research 2015-10, Vol.13 (10_Supplement), p.A02-A02
• Main Authors: Barbieri, Eveline, Chen, Zaowen, Moreno-Smith, Mirthala, Shohet, Jason M.
• Format: Article
• Language: English
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1557-3125.MYC15-A02

Background. Neuroblastoma (NB) arises from embryonal neural crest secondary to a block in differentiation and long-term survival inversely correlates with degree of neuronal differentiation. Metabolic rewiring is an important feature of undifferentiated NB tumors. Interestingly, MYCN down regulation precedes differentiation of NB cells induced by retinoic acid (RA) and genetic MYCN silencing leads to neuronal differentiation. We have recently demonstrated a novel function for the histone chaperone CHAF1A in blocking NB differentiation. CHAF1A is a subunit of the Chromatin Assembly Factor-1 (CAF1), which regulates H3K9-trimethylation and DNA methylation. Methods. Morphological and molecular evaluations of NB differentiation were assessed upon CHAF1A silencing in RA-sensitive and RA-resistant lines by neurite outgrowth assays and Q-PCR for mature neuronal markers. Gene expression profiling of CHAF1A knockdown and control cell lines was performed on the Affymetrix U133+2.0 arrays. GSEA (Gene Set Enrichment Analysis) defined the transcriptional response to CHAF1A silencing in RA sensitive lines. Quantitative-PCR assays were used to validate the most significant enriched metabolic gene sets and MYCN western blotting was performed at different time points after CHAF1A silencing. Results. CHAFIA suppression in MYCN-amplified RA-sensitive and RA-resistant lines results in NB differentiation and inhibition of cell proliferation. CHAF1A silencing significantly (nominal p-value