2. Academic Validation
  3. MBD3 deficiency decommissions the NuRD complex and orchestrates the epigenetic regulation of gene expression to suppress neuroblastoma progression

MBD3 deficiency decommissions the NuRD complex and orchestrates the epigenetic regulation of gene expression to suppress neuroblastoma progression

  • Neuro Oncol. 2026 Jan 7:noaf297. doi: 10.1093/neuonc/noaf297.
Chen Chen 1,  Bize Guo 1,  Siyan Wu 1,  Qinfang Zhu 1,  Hui Shi 2,  Jinhu Wang 1 3 4 5,  Qiang Shu 4,  Ting Tao 3 4 5
Affiliations

Affiliations

  • 1 Pediatric Cancer Research Center, National Clinical Research Center for Child Health, Children's Hospital Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Key Laboratory of Animal Virology of Ministry of Agriculture, College of Animal Sciences, Zhejiang University, Hangzhou, China.
  • 3 Department of Surgical Oncology, Children's Hospital Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
  • 4 Zhejiang Key Laboratory of Neonatal Diseases, Hangzhou, China.
  • 5 Cancer Center, Zhejiang University, Hangzhou, China.
PMID: 41499431 DOI: 10.1093/neuonc/noaf297
Abstract

Background: Neuroblastoma (NB) is the most common extracranial solid tumor in children and accounts for 15% of childhood Cancer death. The nucleosome remodeling and deacetylase (NuRD) complex is a major chromatin remodeling complex that regulates chromatin accessibility and gene transcription. However, its role in the pathogenesis of neuroblastoma remains poorly understood.

Methods: The genetic dependency and clinical significance of MBD3 in neuroblastoma was evaluated by analysis of public datasets. The function of MBD3 in neuroblastoma cell growth was evaluated by shRNA knockdown experiment. Cleavage under targets and tagmentation Sequencing (CUT&Tag-seq), coupled with RNA-sequencing, was employed to explore the mechanisms involved in the epigenetic regulation executed by NuRD decommissioning following MBD3 deficiency.

Results: Here we find that MBD3 is the most lineage-selective dependency among the non-enzymatic subunits of the NuRD complex in neuroblastoma. Knockdown of MBD3 induces cell cycle arrest and Apoptosis, and inhibits neuroblastoma growth in vivo. Mechanistically, MBD3 deficiency leads to decommissioning of the NuRD complex and dissociation of the EZH2-PRC2 complex from chromatin, thereby orchestrating the epigenetic regulation of gene expression by modulating the balance between histone acetylation and methylation. NuRD decommissioning upon MBD3 deficiency selectively downregulates the expression of core regulatory transcription factors and upregulates a tumor suppressor SRCIN1, collectively suppressing neuroblastoma progression.

Conclusions: Our data identify MBD3 and the NuRD complex as potential therapeutic targets in neuroblastoma, highlighting the critical role of epigenetic regulation in tumor maintenance. Targeting this pathway may offer a novel strategy to selectively impair neuroblastoma cell survival and improve outcomes.

Keywords

MBD3; NuRD complex; SRCIN1; neuroblastoma.

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