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Using Caenorhabditis elegans to Screen for Tissue-Specific Chaperone Interactions
Published on: June 7, 2020
Histone chaperone CHAF1A inhibits differentiation and promotes aggressive neuroblastoma
Eveline Barbieri1, Katleen De Preter, Mario Capasso
1Authors' Affiliations: Texas Children's Cancer Center and Center for Cell and Gene Therapy; Department of Surgery, Baylor College of Medicine, Houston, Texas; Center for Medical Genetics, Ghent University, Ghent, Belgium; CEINGE Biotecnologie Avanzate, Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples; Pediatric Research Institute, University of Padua, Padua; Paediatric Oncology and Haematology Unit "Lalla Seràgnoli," Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; and Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
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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