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Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands

Author

Listed:
  • Florian Haller

    (Friedrich-Alexander University Erlangen-Nuremberg)

  • Matthias Bieg

    (Berlin Institute of Health and Charité – Universitätsmedizin Berlin
    Heidelberg Center for Personalized Oncology (DKFZ-HIPO))

  • Rainer Will

    (German Cancer Research Center (DKFZ))

  • Cindy Körner

    (German Cancer Research Center (DKFZ))

  • Dieter Weichenhan

    (German Cancer Research Center (DKFZ))

  • Alexander Bott

    (German Cancer Research Center (DKFZ))

  • Naveed Ishaque

    (Berlin Institute of Health and Charité – Universitätsmedizin Berlin
    Heidelberg Center for Personalized Oncology (DKFZ-HIPO))

  • Pavlo Lutsik

    (German Cancer Research Center (DKFZ))

  • Evgeny A. Moskalev

    (Friedrich-Alexander University Erlangen-Nuremberg)

  • Sarina K. Mueller

    (Friedrich-Alexander University Erlangen-Nuremberg)

  • Marion Bähr

    (German Cancer Research Center (DKFZ))

  • Angelika Woerner

    (German Cancer Research Center (DKFZ))

  • Birgit Kaiser

    (German Cancer Research Center (DKFZ))

  • Claudia Scherl

    (Friedrich-Alexander University Erlangen-Nuremberg)

  • Marlen Haderlein

    (Friedrich-Alexander University Erlangen-Nuremberg)

  • Kortine Kleinheinz

    (German Cancer Research Center (DKFZ))

  • Rainer Fietkau

    (Friedrich-Alexander University Erlangen-Nuremberg)

  • Heinrich Iro

    (Friedrich-Alexander University Erlangen-Nuremberg)

  • Roland Eils

    (Berlin Institute of Health and Charité – Universitätsmedizin Berlin
    Heidelberg Center for Personalized Oncology (DKFZ-HIPO)
    University Hospital Heidelberg
    University of Heidelberg)

  • Arndt Hartmann

    (Friedrich-Alexander University Erlangen-Nuremberg)

  • Christoph Plass

    (German Cancer Research Center (DKFZ))

  • Stefan Wiemann

    (German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ))

  • Abbas Agaimy

    (Friedrich-Alexander University Erlangen-Nuremberg)

Abstract

The molecular pathogenesis of salivary gland acinic cell carcinoma (AciCC) is poorly understood. The secretory Ca-binding phosphoprotein (SCPP) gene cluster at 4q13 encodes structurally related phosphoproteins of which some are specifically expressed at high levels in the salivary glands and constitute major components of saliva. Here we report on recurrent rearrangements [t(4;9)(q13;q31)] in AciCC that translocate active enhancer regions from the SCPP gene cluster to the region upstream of Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3) at 9q31. We show that NR4A3 is specifically upregulated in AciCCs, and that active chromatin regions and gene expression signatures in AciCCs are highly correlated with the NR4A3 transcription factor binding motif. Overexpression of NR4A3 in mouse salivary gland cells increases expression of known NR4A3 target genes and has a stimulatory functional effect on cell proliferation. We conclude that NR4A3 is upregulated through enhancer hijacking and has important oncogenic functions in AciCC.

Suggested Citation

  • Florian Haller & Matthias Bieg & Rainer Will & Cindy Körner & Dieter Weichenhan & Alexander Bott & Naveed Ishaque & Pavlo Lutsik & Evgeny A. Moskalev & Sarina K. Mueller & Marion Bähr & Angelika Woern, 2019. "Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-08069-x
    DOI: 10.1038/s41467-018-08069-x
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    Cited by:

    1. Josefine Radke & Naveed Ishaque & Randi Koll & Zuguang Gu & Elisa Schumann & Lina Sieverling & Sebastian Uhrig & Daniel Hübschmann & Umut H. Toprak & Cristina López & Xavier Pastor Hostench & Simone B, 2022. "The genomic and transcriptional landscape of primary central nervous system lymphoma," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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