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

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Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands.
Nature Communications ( IF 14.7 ) Pub Date : 2019-01-21 , DOI: 10.1038/s41467-018-08069-x
Florian Haller ₁ , Matthias Bieg _{2,

3} , Rainer Will ₄ , Cindy Körner ₅ , Dieter Weichenhan ₆ , Alexander Bott ₅ , Naveed Ishaque _{2,

3} , Pavlo Lutsik ₆ , Evgeny A Moskalev ₁ , Sarina K Mueller ₇ , Marion Bähr ₆ , Angelika Woerner ₅ , Birgit Kaiser ₄ , Claudia Scherl ₇ , Marlen Haderlein ₈ , Kortine Kleinheinz ₉ , Rainer Fietkau ₈ , Heinrich Iro ₇ , Roland Eils _{2,

3,

10,

11} , Arndt Hartmann ₁ , Christoph Plass ₆ , Stefan Wiemann _{4,

5} , Abbas Agaimy ₁

Affiliation

Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054, Erlangen, Germany.
Center for Digital Health, Berlin Institute of Health and Charité - Universitätsmedizin Berlin, Kapelle-Ufer 2, 10117, Berlin, Germany.
Heidelberg Center for Personalized Oncology (DKFZ-HIPO), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Department of Otorhinolaryngology, Head & Neck Surgery, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Waldstrasse 1, 91054, Erlangen, Germany.
Department of Radiation Therapy, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Universitätsstrasse 27, 91054, Erlangen, Germany.
Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Health Data Science Unit, University Hospital Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany.
Translational Lung Research Center Heidelberg, German Center for Lung Research, University of Heidelberg, Im Neuenheimer Feld 156, 69120 Heidelberg, Germany.

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.

中文翻译：

增强子劫持会激活唾液腺腺泡细胞癌中的致癌转录因子 NR4A3。

唾液腺腺泡细胞癌（AciCC）的分子发病机制尚不清楚。位于 4q13 的分泌性 Ca 结合磷蛋白 (SCPP) 基因簇编码结构相关的磷蛋白，其中一些在唾液腺中高水平特异性表达，并构成唾液的主要成分。在这里，我们报告了 AciCC 中的反复重排 [t(4;9)(q13;q31)]，这些重排将活性增强子区域从 SCPP 基因簇易位到核受体亚家族 4 A 组成员 3 (NR4A3) 9q31 的上游区域。我们发现 NR4A3 在 AciCC 中特异性上调，并且 AciCC 中的活性染色质区域和基因表达特征与 NR4A3 转录因子结合基序高度相关。小鼠唾液腺细胞中 NR4A3 的过度表达会增加已知 NR4A3 靶基因的表达，并对细胞增殖具有刺激功能作用。我们得出的结论是，NR4A3 通过增强子劫持而上调，并且在 AciCC 中具有重要的致癌功能。

更新日期：2019-01-23

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