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Nat Commun. 2019 Jan 21;10(1):368. doi: 10.1038/s41467-018-08069-x.

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

Author information

1
Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054, Erlangen, Germany. florian.haller@uk-erlangen.de.
2
Center for Digital Health, Berlin Institute of Health and Charité - Universitätsmedizin Berlin, Kapelle-Ufer 2, 10117, Berlin, Germany.
3
Heidelberg Center for Personalized Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
4
Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
5
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
6
Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
7
Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054, Erlangen, Germany.
8
Department of Otorhinolaryngology, Head & Neck Surgery, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Waldstrasse 1, 91054, Erlangen, Germany.
9
Department of Radiation Therapy, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Universitätsstrasse 27, 91054, Erlangen, Germany.
10
Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
11
Health Data Science Unit, University Hospital Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany.
12
Translational Lung Research Center Heidelberg, German Center for Lung Research, University of Heidelberg, Im Neuenheimer Feld 156, 69120 Heidelberg, Germany.
13
Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany. s.wiemann@dkfz-heidelberg.de.
14
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany. s.wiemann@dkfz-heidelberg.de.

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.

PMID:
30664630
PMCID:
PMC6341107
DOI:
10.1038/s41467-018-08069-x
[Indexed for MEDLINE]
Free PMC Article

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