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

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 Woerner, Birgit Kaiser, Claudia Scherl, Marlen Haderlein, Kortine Kleinheinz, Rainer Fietkau, Heinrich Iro, Roland Eils, Arndt Hartmann, Christoph Plass, Stefan Wiemann () and Abbas Agaimy
Additional contact information
Florian Haller: Friedrich-Alexander University Erlangen-Nuremberg
Matthias Bieg: Berlin Institute of Health and Charité – Universitätsmedizin Berlin
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
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
Arndt Hartmann: Friedrich-Alexander University Erlangen-Nuremberg
Christoph Plass: German Cancer Research Center (DKFZ)
Stefan Wiemann: German Cancer Research Center (DKFZ)
Abbas Agaimy: Friedrich-Alexander University Erlangen-Nuremberg

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08069-x

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