AKNA drives neuroblastoma cell fate transition through chromatin modifications of stemness factors and differentiation by cytosolic retention.

Abstract

Neuroblast cells play a pivotal role in adult neurogenesis. However, the detailed mechanisms underlying the acquisition of pluripotency or the process of differentiation remain unknown. Herein, the role of the AT-hook protein AKNA in regulating pluripotency and stemness in neuroblastoma cells is demonstrated through gene knockdown, immunofluorescence, chromatin immunoprecipitation (ChIP), localization of AKNA, signaling interactions, and transcriptional activity. AKNA was detected primarily in the nucleus during the induction of pluripotency and was retained in the cytosol by FAK signaling during differentiation. Loss of AKNA disrupts both the stemness and differentiation potential of neuroblastoma cells. In the nucleus, colocalization and physical association between AKNA and KDM6B promote H3K27me3 demethylation and subsequently H3K27ac deposition on the promoters of stemness genes, triggering their transcription. These findings establish AKNA as a critical regulator of neuroblast cell fate determinants in association with epigenetic modifiers and signaling pathways, offering potential targets for neuroblastoma therapies and regenerative medicine for neurodegenerative diseases.