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KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma

Author

Listed:
  • Alexandra D’Oto

    (St. Jude Children’s Research Hospital)

  • Jie Fang

    (St. Jude Children’s Research Hospital)

  • Hongjian Jin

    (St. Jude Children’s Research Hospital)

  • Beisi Xu

    (St. Jude Children’s Research Hospital)

  • Shivendra Singh

    (St. Jude Children’s Research Hospital)

  • Anoushka Mullasseril

    (St. Jude Children’s Research Hospital)

  • Victoria Jones

    (St. Jude Children’s Research Hospital)

  • Ahmed Abu-Zaid

    (St. Jude Children’s Research Hospital)

  • Xinyu Buttlar

    (St. Jude Children’s Research Hospital)

  • Bailey Cooke

    (St. Jude Children’s Research Hospital)

  • Dongli Hu

    (St. Jude Children’s Research Hospital)

  • Jason Shohet

    (University of Massachusetts Medical School)

  • Andrew J. Murphy

    (St. Jude Children’s Research Hospital)

  • Andrew M. Davidoff

    (St. Jude Children’s Research Hospital)

  • Jun Yang

    (St. Jude Children’s Research Hospital)

Abstract

The H3K27me2/me3 histone demethylase KDM6B is essential to neuroblastoma cell survival. However, the mechanism of KDM6B action remains poorly defined. We demonstrate that inhibition of KDM6B activity 1) reduces the chromatin accessibility of E2F target genes and MYCN, 2) selectively leads to an increase of H3K27me3 but a decrease of the enhancer mark H3K4me1 at the CTCF and BORIS binding sites, which may, consequently, disrupt the long-range chromatin interaction of MYCN and E2F target genes, and 3) phenocopies the transcriptome induced by the specific CDK4/6 inhibitor palbociclib. Overexpression of CDK4/6 or Rb1 knockout confers neuroblastoma cell resistance to both palbociclib and the KDM6 inhibitor GSK-J4. These data indicate that KDM6B promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma.

Suggested Citation

  • Alexandra D’Oto & Jie Fang & Hongjian Jin & Beisi Xu & Shivendra Singh & Anoushka Mullasseril & Victoria Jones & Ahmed Abu-Zaid & Xinyu Buttlar & Bailey Cooke & Dongli Hu & Jason Shohet & Andrew J. Mu, 2021. "KDM6B promotes activation of the oncogenic CDK4/6-pRB-E2F pathway by maintaining enhancer activity in MYCN-amplified neuroblastoma," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27502-2
    DOI: 10.1038/s41467-021-27502-2
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