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

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Summary

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.

Graphical abstract

Highlights

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MYCN promotes KDM4 induction and cellular state switch from mesenchymal to adrenergic
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KDM4 inhibition induces H3K9me3 and blocks MYCN and adrenergic transcriptome
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KDM4 inhibition leads to significant suppression of neuroblastoma growth
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KDM4 inhibition in combination with chemotherapy results in complete tumor responses

Abstract

Abu-Zaid et al. show that KDM4 inhibition blocks MYCN function in high-risk neuroblastoma models. The combination of a selective KDM4 inhibitor with chemotherapy reduces tumor growth of neuroblastoma xenografts.

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Author and article information

Contributors

Jun Yang

Journal

Journal ID (nlm-ta): Cell Rep Med

Journal ID (iso-abbrev): Cell Rep Med

Title: Cell Reports Medicine

Publisher: Elsevier

ISSN (Electronic): 2666-3791

Publication date PMC-release: 21 March 2024

Publication date Collection: 19 March 2024

Publication date (Electronic): 21 March 2024

Volume: 5

Issue: 3

Electronic Location Identifier: 101468

Affiliations

[1 ]Department of Surgery, St Jude Children’s Research Hospital, Memphis, TN 38105, USA

[2 ]Center for Applied Bioinformatics, St Jude Children’s Research Hospital, Memphis, TN 38105, USA

[3 ]Department of Pathology, St Jude Children’s Research Hospital, Memphis, TN 38105, USA

[4 ]Department of Immunology, St Jude Children’s Research Hospital, Memphis, TN 38105, USA

[5 ]Department of Biostatistics, St Jude Children’s Research Hospital, Memphis, TN 38105, USA

[6 ]Department of Molecular Oncology, St Jude Children’s Research Hospital, Memphis, TN 38105, USA

[7 ]Department of Chemical Biology and Therapeutics, St Jude Children’s Research Hospital, Memphis, TN 38105, USA

[8 ]Department of Computational Biology, St Jude Children’s Research Hospital, Memphis, TN 38105, USA

[9 ]Genetics, Genomics & Informatics, The University of Tennessee Health Science Center, Memphis, TN 38103, USA

[10 ]Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany

[11 ]Division of Pediatric Surgery, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN 38105, USA

[12 ]St Jude Graduate School of Biomedical Sciences, St Jude Children’s Research Hospital, Memphis, TN 38105, USA

[13 ]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 ]College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN, USA

Author notes

[∗ ]Corresponding author jun.yang2@ 123456stjude.org

[15]

These authors contributed equally

[16]

Lead contact

Article

Publisher Item ID: S2666-3791(24)00114-9 Publisher ID: 101468

DOI: 10.1016/j.xcrm.2024.101468

PMC ID: 10983111

PubMed ID: 38508144

SO-VID: 0f7aab15-c55d-4db6-8fd9-05d12c787ca9

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 22 August 2022

Date revision received : 21 December 2023

Date accepted : 20 February 2024

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