Related Experiment Video

Updated: May 10, 2025

Zebrafish Model of Neuroblastoma Metastasis
05:20

Zebrafish Model of Neuroblastoma Metastasis

Published on: March 14, 2021

2.7K

MYCN and KAT2A form a feedforward loop to drive an oncogenic transcriptional program in neuroblastoma

Zhihui Liu1, Jason J Hong2, Xiyuan Zhang2

  • 1Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA. liuzhihu@mail.nih.gov.

Oncogenesis
|April 24, 2025
PubMed

Insights

MYCN drives neuroblastoma malignancy. We found MYCN partners with KAT2A, forming a feedforward loop that boosts cancer growth. Targeting KAT2A with PROTACs reduced MYCN and suppressed neuroblastoma cell proliferation, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Regulation

Background:

  • The oncoprotein MYCN is a key driver of neuroblastoma (NB) malignancy.
  • Mechanisms of MYCN's transcriptional activity and oncogenic functions are not fully understood.
  • Targeting MYCN effectively remains a challenge in NB therapy.

Purpose of the Study:

  • To elucidate the role of MYCN's interaction with transcriptional coactivators in NB.
  • To investigate the functional consequences of the MYCN-KAT2A interaction in NB.
  • To explore KAT2A as a potential therapeutic target for NB.

Main Methods:

  • Genome-wide analyses to identify MYCN-recruited factors.
  • Chromatin immunoprecipitation sequencing (ChIP-seq) to assess DNA binding.
  • Western blotting and acetylation assays to evaluate protein stability and modification.
  • Cell proliferation assays and PROTAC-mediated degradation studies.

Main Results:

  • MYCN interacts with the transcriptional coactivator KAT2A, enhancing its activity in NB.
  • MYCN recruits KAT2A for DNA binding, regulating genes involved in ribosome biogenesis and RNA processing.
  • A feedforward loop exists where MYCN activates KAT2A transcription and KAT2A stabilizes MYCN protein.
  • KAT2A Proteolysis Targeting Chimera (PROTAC) treatment reduced MYCN levels, inhibited MYCN-driven transcription, and suppressed NB cell proliferation.

Conclusions:

  • The MYCN-KAT2A interaction is crucial for regulating global gene expression and driving the NB phenotype.
  • Transcriptional cofactors like KAT2A represent promising therapeutic targets for anti-MYCN strategies.
  • Targeting KAT2A with PROTACs offers a viable approach to antagonize MYCN activity and treat neuroblastoma.

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