Histone chaperone CHAF1A inhibits differentiation and promotes aggressive neuroblastoma

Eveline Barbieri, Katleen De Preter, Mario Capasso, Zaowen Chen, Danielle M. Hsu, Gian Paolo Tonini, Steve Lefever, John Hicks, Rogier Versteeg, Andrea Pession, Frank Speleman, Eugene S. Kim, Jason M. Shohet

Research output: Contribution to journalArticle

Abstract

Neuroblastoma arises from the embryonal neural crest secondary to a block in differentiation. Long-term patient survival correlates inversely with the extent of differentiation, and treatment with retinoic acid or other prodifferentiation agents improves survival modestly. In this study, we show the histone chaperone and epigenetic regulator CHAF1A functions in maintaining the highly dedifferentiated state of this aggressive malignancy. CHAF1A is a subunit of the chromatin modifier chromatin assembly factor 1 and it regulates H3K9 trimethylation of key target genes regulating proliferation, survival, and differentiation. Elevated CHAF1A expression strongly correlated with poor prognosis. Conversely, CHAF1A loss-of-function was sufficient to drive neuronal differentiation in vitro and in vivo. Transcriptome analysis of cells lacking CHAF1A revealed repression of oncogenic signaling pathways and a normalization of glycolytic metabolism. Our findings demonstrate that CHAF1A restricts neural crest differentiation and contributes to the pathogenesis of high-risk neuroblastoma.

Original languageEnglish
Pages (from-to)765-774
Number of pages10
JournalCancer Research
Volume74
Issue number3
DOIs
Publication statusPublished - Feb 1 2014

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Barbieri, E., De Preter, K., Capasso, M., Chen, Z., Hsu, D. M., Tonini, G. P., Lefever, S., Hicks, J., Versteeg, R., Pession, A., Speleman, F., Kim, E. S., & Shohet, J. M. (2014). Histone chaperone CHAF1A inhibits differentiation and promotes aggressive neuroblastoma. Cancer Research, 74(3), 765-774. https://doi.org/10.1158/0008-5472.CAN-13-1315