Histone chaperone CHAF1A inhibits differentiation and promotes aggressive neuroblastoma.

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.

• Authors: 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
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 3 Pg. 765-74 (Feb 01 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 24335960 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CNOT8 protein, human
• Chromatin Assembly Factor-1
• Histones
• Transcription Factors
• Tumor Suppressor Protein p53

Topics

• Animals
• Cell Differentiation (genetics)
• Cell Transformation, Neoplastic (genetics)
• Chromatin Assembly Factor-1 (genetics, metabolism)
• Cluster Analysis
• Cohort Studies
• Disease Models, Animal
• Disease Progression
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Histones (metabolism)
• Humans
• Mice
• Neuroblastoma (genetics, metabolism, mortality, pathology)
• Signal Transduction
• Transcription Factors
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Xenograft Model Antitumor Assays