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

Haller F, Bieg M, Will R, Koerner C, Weichenhan D, Bott A, Ishaque N, Lutsik P, Moskalev E, Müller S, Baehr M, Woerner A, Kaiser B, Scherl C, Haderlein M, Kleinheinz K, Fietkau R, Iro H, Eils R, Hartmann A, Plass C, Wiemann S, Agaimy A (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 10

Journal Issue: 1

DOI: 10.1038/s41467-018-08069-x

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.

Authors with CRIS profile

Evgeny Moskalev Institute of Pathology Marlen Haderlein Department of Radiation Oncology Rainer Fietkau Lehrstuhl für Strahlentherapie Heinrich Iro Lehrstuhl für Hals-, Nasen- und Ohrenheilkunde Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Abbas Agaimy Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie

Involved external institutions

Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Charité - Universitätsmedizin Berlin DE Germany (DE)

How to cite

APA:

Haller, F., Bieg, M., Will, R., Koerner, C., Weichenhan, D., Bott, A.,... Agaimy, A. (2019). Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands. Nature Communications, 10(1). https://dx.doi.org/10.1038/s41467-018-08069-x

MLA:

Haller, Florian, et al. "Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands." Nature Communications 10.1 (2019).

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