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Review

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

by
Sofya S. Pogodaeva
1,†,
Olga O. Miletina
1,†,
Nadezhda V. Antipova
2,
Alexander A. Shtil
3,4 and
Oleg A. Kuchur
1,5,*
1
Center for Molecular and Biological Technologies, ITMO University, 197101 Saint Petersburg, Russia
2
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
3
Blokhin National Medical Research Center of Oncology, 115522 Moscow, Russia
4
National Research Nuclear University MEPhI, 115409 Moscow, Russia
5
Higher School of Economics, 194100 Saint Petersburg, Russia
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2025, 17(19), 3228; https://doi.org/10.3390/cancers17193228
Submission received: 2 September 2025 / Revised: 28 September 2025 / Accepted: 2 October 2025 / Published: 3 October 2025
(This article belongs to the Special Issue Precision Medicine and Targeted Therapies in Neuroblastoma)

Simple Summary

Neuroblastoma is a dangerous childhood cancer where many genes are in the “on” position, driving an uncontrolled tumor growth. A multifunctional non-POU domain-containing octamer-binding protein (NONO) acts as a master regulator of these genes. Therefore, NONO emerges as a key culprit of the disease’s aggressiveness and resistance to therapy. This review explores how targeting NONO could offer new therapeutic strategies. We discuss the challenges of drug development and highlight recent development of chemical tools to inhibit NONO function. Successful targeting of NONO is expected to provide powerful new treatments for children with high-risk neuroblastoma, potentially overcoming the limitations of current therapies.

Abstract

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: gene transcription; core regulatory circuit; NONO; MYCN; long non-coding RNAs; therapeutic target; neuroblastoma; cancer gene transcription; core regulatory circuit; NONO; MYCN; long non-coding RNAs; therapeutic target; neuroblastoma; cancer

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MDPI and ACS Style

Pogodaeva, S.S.; Miletina, O.O.; Antipova, N.V.; Shtil, A.A.; Kuchur, O.A. Saying “Yes” to NONO: A Therapeutic Target for Neuroblastoma and Beyond. Cancers 2025, 17, 3228. https://doi.org/10.3390/cancers17193228

AMA Style

Pogodaeva SS, Miletina OO, Antipova NV, Shtil AA, Kuchur OA. Saying “Yes” to NONO: A Therapeutic Target for Neuroblastoma and Beyond. Cancers. 2025; 17(19):3228. https://doi.org/10.3390/cancers17193228

Chicago/Turabian Style

Pogodaeva, Sofya S., Olga O. Miletina, Nadezhda V. Antipova, Alexander A. Shtil, and Oleg A. Kuchur. 2025. "Saying “Yes” to NONO: A Therapeutic Target for Neuroblastoma and Beyond" Cancers 17, no. 19: 3228. https://doi.org/10.3390/cancers17193228

APA Style

Pogodaeva, S. S., Miletina, O. O., Antipova, N. V., Shtil, A. A., & Kuchur, O. A. (2025). Saying “Yes” to NONO: A Therapeutic Target for Neuroblastoma and Beyond. Cancers, 17(19), 3228. https://doi.org/10.3390/cancers17193228

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