Histone chaperone CHAF1A inhibits differentiation and promotes aggressive neuroblastoma

Cancer Research
Eveline BarbieriJason M Shohet

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.

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Citations

Oct 22, 2014·Nature Reviews. Clinical Oncology·Garrett M Brodeur, Rochelle Bagatell
Jan 8, 2016·Biochemical and Biophysical Research Communications·Honghai PengJun Gao
May 23, 2014·Biochemical and Biophysical Research Communications·Zehua WuZhihai Peng
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Feb 17, 2019·Cellular and Molecular Life Sciences : CMLS·Aroa SorianoMiguel F Segura
Sep 17, 2020·European Journal of Medicinal Chemistry·Zegao JinXiaowu Dong
Nov 14, 2018·Cancer Cell·Andrew VolkJohn D Crispino

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