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A “cooperative collaboration” between HAND2 and MYCN shapes neuroblastoma cell identity

Man Xu, Ming Sun, Xiyuan Zhang, Rosa Nguyen, Haiyan Lei, Jack F. Shern, Carol J. Thiele, View ORCID ProfileZhihui Liu
doi: https://doi.org/10.1101/2022.05.18.492511
Man Xu
1Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA
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Ming Sun
1Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA
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Xiyuan Zhang
1Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA
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Rosa Nguyen
1Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA
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Haiyan Lei
1Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA
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Jack F. Shern
1Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA
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Carol J. Thiele
1Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA
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  • For correspondence: liuzhihu@mail.nih.gov thielec@mail.nih.gov
Zhihui Liu
1Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA
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  • ORCID record for Zhihui Liu
  • For correspondence: liuzhihu@mail.nih.gov thielec@mail.nih.gov
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ABSTRACT

Noradrenergic neuroblastoma (NB) is characterized by a core transcriptional regulatory circuitry (CRC) comprised of transcription factors (TFs) such as PHOX2B, HAND2 and GATA3, which form a network with MYCN. Physiological levels of MYCN mainly binds to promoters but aberrantly upregulated MYCN in NB also binds to enhancers. How MYCN invades enhancers, and what role the CRC TFs play in this process is unknown. Here we find that HAND2 assists MYCN to invade enhancers through an “indirect cooperative” TF-DNA binding mechanism. HAND2 cooperates with MYCN to compete with nucleosomes and regulate global gene transcription. The treatment of NB with an Aurora A kinase inhibitor plus HDAC inhibitor potently downregulates both MYCN and the CRC TFs and suppresses MYCN-amplified NB tumor growth. Our study identifies a “cooperative collaboration” among MYCN and CRC TFs and the simultaneous targeting these TFs is an effective way to treat this aggressive pediatric tumor.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 20, 2022.
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A “cooperative collaboration” between HAND2 and MYCN shapes neuroblastoma cell identity
Man Xu, Ming Sun, Xiyuan Zhang, Rosa Nguyen, Haiyan Lei, Jack F. Shern, Carol J. Thiele, Zhihui Liu
bioRxiv 2022.05.18.492511; doi: https://doi.org/10.1101/2022.05.18.492511
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A “cooperative collaboration” between HAND2 and MYCN shapes neuroblastoma cell identity
Man Xu, Ming Sun, Xiyuan Zhang, Rosa Nguyen, Haiyan Lei, Jack F. Shern, Carol J. Thiele, Zhihui Liu
bioRxiv 2022.05.18.492511; doi: https://doi.org/10.1101/2022.05.18.492511

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