Saying “Yes” to NONO: A Therapeutic Target for Neuroblastoma and Beyond

Cancers. 2025. Vol. 17. No. 19. Article 3228.

Pogodaeva S., Miletina O., Antipova N., Shtil A., Oleg A. Kuchur

Pediatric tumors such as neuroblastoma are characterized by a genome-wide ‘transcriptional burden’, surmising the involvement of multiple alterations of gene expression. Search for master regulators of transcription whose inactivation is lethal for tumor cells identified the non-POU domain-containing octamer-binding protein (NONO), a member of the Drosophila Behavior/Human Splicing family known for the ability to form complexes with macromolecules. NONO emerges as an essential mechanism in normal neurogenesis as well as in tumor biology. In particular, NONO interactions with RNAs, largely with long non-coding MYCN transcripts, have been attributed to the aggressiveness of neuroblastoma. Broadening its significance beyond MYCN regulation, NONO guards a subset of transcription factors that comprise a core regulatory circuit, a self-sustained loop that maintains transcription. As a component of protein–protein complexes, NONO has been implicated in the control of cell cycle progression, double-strand DNA repair, and, generally, in cell survival. Altogether, the pro-oncogenic roles of NONO justify the need for its inactivation as a therapeutic strategy. However, considering NONO as a therapeutic target, its druggability is a challenge. Recent advances in the inactivation of NONO and downstream signaling with small molecular weight compounds make promising the development of pharmacological antagonists of NONO pathway(s) for neuroblastoma treatment.

Keywords: cancer, Long non-coding RNAs, MYCN, neuroblastoma, core regulatory circuit, NONO, therapeutic target, gene transcription