2. Academic Validation
  3. Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma

Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma

  • Cell Rep Med. 2024 Mar 19;5(3):101468. doi: 10.1016/j.xcrm.2024.101468.
Ahmed Abu-Zaid 1,  Jie Fang 2,  Hongjian Jin 3,  Shivendra Singh 2,  Prahalathan Pichavaram 2,  Qiong Wu 2,  Heather Tillman 4,  Laura Janke 4,  Wojciech Rosikiewicz 3,  Beisi Xu 3,  Lee-Ann Van De Velde 5,  Yian Guo 6,  Yimei Li 6,  Noha A M Shendy 7,  Ian M Delahunty 7,  Zoran Rankovic 8,  Taosheng Chen 8,  Xiang Chen 9,  Kevin W Freeman 10,  Mark E Hatley 7,  Adam D Durbin 7,  Peter J Murray 11,  Andrew J Murphy 12,  Paul G Thomas 5,  Andrew M Davidoff 13,  Jun Yang 14
Affiliations

Affiliations

  • 1 Department of Surgery, St Jude Children's Research Hospital, Memphis, TN 38105, USA; College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN, USA.
  • 2 Department of Surgery, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 3 Center for Applied Bioinformatics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 4 Department of Pathology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 5 Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 6 Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 7 Department of Molecular Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 8 Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 9 Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 10 Genetics, Genomics & Informatics, The University of Tennessee Health Science Center, Memphis, TN 38103, USA.
  • 11 Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
  • 12 Department of Surgery, St Jude Children's Research Hospital, Memphis, TN 38105, USA; Division of Pediatric Surgery, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN 38105, USA.
  • 13 Department of Surgery, St Jude Children's Research Hospital, Memphis, TN 38105, USA; Division of Pediatric Surgery, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN 38105, USA; St Jude Graduate School of Biomedical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Pathology and Laboratory Medicine, College of Medicine, The University of Tennessee Health Science Center, 930 Madison Avenue, Suite 500, Memphis, TN 38163, USA.
  • 14 Department of Surgery, St Jude Children's Research Hospital, Memphis, TN 38105, USA; St Jude Graduate School of Biomedical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Pathology and Laboratory Medicine, College of Medicine, The University of Tennessee Health Science Center, 930 Madison Avenue, Suite 500, Memphis, TN 38163, USA; College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN, USA. Electronic address: [email protected].
PMID: 38508144 DOI: 10.1016/j.xcrm.2024.101468
Abstract

Neuroblastoma with MYCN amplification (MNA) is a high-risk disease that has a poor survival rate. Neuroblastoma displays cellular heterogeneity, including more differentiated (adrenergic) and more primitive (mesenchymal) cellular states. Here, we demonstrate that MYCN oncoprotein promotes a cellular state switch in mesenchymal cells to an adrenergic state, accompanied by induction of histone lysine demethylase 4 family members (KDM4A-C) that act in concert to control the expression of MYCN and adrenergic core regulatory circulatory (CRC) transcription factors. Pharmacologic inhibition of KDM4 blocks expression of MYCN and the adrenergic CRC transcriptome with genome-wide induction of transcriptionally repressive H3K9me3, resulting in potent Anticancer activity against neuroblastomas with MNA by inducing neuroblastic differentiation and Apoptosis. Furthermore, a short-term KDM4 inhibition in combination with conventional, cytotoxic chemotherapy results in complete tumor responses of xenografts with MNA. Thus, KDM4 blockade may serve as a transformative strategy to target the adrenergic CRC dependencies in MNA neuroblastomas.

Keywords

KDM4; MYCN; QC6352; cell state switch; core regulatory circuitry; neuroblastoma.

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