title: 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: Authors' 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.
authors: Eveline
authors: E
authors: Barbieri
authors: Katleen
authors: K
authors: De Preter
authors: Mario
authors: M
authors: Capasso
authors: Zaowen
authors: Z
authors: Chen
authors: Danielle M
authors: DM
authors: Hsu
authors: Gian Paolo
authors: GP
authors: Tonini
authors: Steve
authors: S
authors: Lefever
authors: John
authors: J
authors: Hicks
authors: Rogier
authors: R
authors: Versteeg
authors: Andrea
authors: A
authors: Pession
authors: Frank
authors: F
authors: Speleman
authors: Eugene S
authors: ES
authors: Kim
authors: Jason M
authors: JM
authors: Shohet
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D056504:Chromatin Assembly Factor-1 / Q000235:genetics* / Q000378:metabolism; D016000:Cluster Analysis; D015331:Cohort Studies; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D015398:Signal Transduction; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C489780:CNOT8 protein, human; D056504:Chromatin Assembly Factor-1; D006657:Histones; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53