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MYCN driven oncogenesis involves cooperation with WDR5 to activate canonical MYC targets and G9a to repress

Zhihui Liu1, Xiyuan Zhang1, Man Xu1

  • 1Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA.

Biorxiv : the Preprint Server for Biology
|October 2, 2023
PubMed

Insights

MYCN drives neuroblastoma by activating growth genes and repressing neuronal genes. Targeting MYCN cofactors WDR5 and G9a simultaneously halts tumor growth, offering a new therapeutic strategy.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • MYCN (Myc-associated factor X) is a key oncogenic driver in neuroblastoma (NB), a pediatric cancer.
  • MYCN's role in regulating gene expression is complex, involving activation of growth-related genes and repression of differentiation genes.
  • The precise mechanisms by which MYCN orchestrates global gene expression and its interactions with epigenetic modifiers are not fully understood.

Approach:

  • Investigated MYCN's binding patterns at promoters and enhancers in neuroblastoma cells.
  • Analyzed changes in histone modifications (H3K4me3, H3K27ac) associated with MYCN binding.
  • Identified cofactor proteins (WDR5, G9a) involved in MYCN's distinct transcriptional activities.
  • Assessed the therapeutic potential of inhibiting MYCN cofactors.

Key Points:

  • MYCN activates canonical targets at promoters, increasing H3K4me3 and H3K27ac marks.
  • MYCN represses neuronal differentiation genes at enhancers and promoters, decreasing H3K27ac.
  • WDR5 facilitates MYCN's activation of target genes, while G9a mediates repression.
  • Combined inhibition of WDR5 and G9a synergistically suppresses neuroblastoma growth.

Conclusions:

  • MYCN cooperates with WDR5 and G9a to control global gene transcription in neuroblastoma.
  • Targeting both WDR5 and G9a represents a novel therapeutic strategy to inhibit MYCN's oncogenic functions.
  • This dual-cofactor targeting approach offers a promising avenue for neuroblastoma treatment.

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