Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands
Authors
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, Abbas Agaimy
Institution
German Cancer Research Center (DKFZ), Heidelberg
Country
Germany
Year
2019
Journal
Nature Communications
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.