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CHAF1A Blocks Neuronal Differentiation and Promotes Neuroblastoma Oncogenesis via Metabolic Reprogramming

ABSTRACT: Neuroblastoma (NB) arises from neural crest cells (NCCs) secondary to a block in differentiation. Retinoic acid (RA) differentiation therapy has limited therapeutic efficacy, and the mechanisms preventing terminal differentiation remain elusive. We found that the chromatin modifier CHAF1A restricts neuronal differentiation and promotes NB oncogenesis. CHAF1A blocks NC differentiation into mature neurons in both human NCCs and zebrafish models. CHAF1A gain-of-function promotes cell malignancy, blocks RA-induced differentiation, and is sufficient to induce NB tumor formation. Mechanistically, CHAF1A blocks NB differentiation by repressing gene expression programs promoting neuronal development and differentiation, and rewiring polyamine metabolism. Targeting polyamine synthesis restores NB sensitivity to RA therapy. Our results demonstrate that CHAF1A critically contributes to NB oncogenesis by blocking neuronal differentiation and reprogramming cell metabolism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144311 | GEO | 2021/07/20

REPOSITORIES: GEO

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CHAF1A Blocks Neuronal Differentiation and Promotes Neuroblastoma Oncogenesis via Metabolic Reprogramming

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