Journal Article

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

Moskalev, Evgeny A., Hartmann, Arndt, Wiemann, Stefan, Agaimy, Abbas, Weichenhan, Dieter, Mueller, Sarina K., Plass, Christoph, Körner, Cindy, Bieg, Matthias, Kaiser, Birgit, Scherl, Claudia, Fietkau, Rainer, Lutsik, Pavlo, Will, Rainer, Ishaque, Naveed, Kleinheinz, Kortine, Iro, Heinrich, Haller, Florian, Eils, Roland, Haderlein, Marlen, Bähr, Marion, Woerner, Angelika, Bott, Alexander

2019

Overview

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. Acinic cell carcinoma (AciCC) is a rare salivary gland carcinoma that is poorly understood. Here the authors perform genomic, transcriptomic and epigenomic profiling of AciCC and find highly recurrent and specific rearrangements [t(4;9)(q13;q31)], which lead to enhancer hijacking that activates oncogenic transcription factor NR4A3.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/15 / 45/23 / 45/91 / 49/39 / 631/208/177 / 631/67/1536 / 631/67/68/2486 / 631/67/69 / Acinar Cells - metabolism / Acinar Cells - pathology / Animals / Binding / Carcinoma / Carcinoma, Acinar Cell - genetics / Carcinoma, Acinar Cell - metabolism / Carcinoma, Acinar Cell - pathology / Cell Proliferation / Chromatin / Chromatin - chemistry / Chromatin - metabolism / Chromosome 4 / Chromosomes, Human, Pair 4 - chemistry / Chromosomes, Human, Pair 4 - metabolism / Chromosomes, Human, Pair 9 - chemistry / Chromosomes, Human, Pair 9 - metabolism / Cohort Studies / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Enhancer Elements, Genetic / Epigenesis, Genetic / Female / Gene expression / Gene Expression Regulation, Neoplastic / Genetic Loci / Humanities and Social Sciences / Humans / Male / Mice / multidisciplinary / Multigene Family / Oral cancer / Pathogenesis / Phosphoproteins / Primary Cell Culture / Receptors, Steroid - genetics / Receptors, Steroid - metabolism / Receptors, Thyroid Hormone - genetics / Receptors, Thyroid Hormone - metabolism / Saliva / Salivary gland / Salivary Gland Neoplasms - genetics / Salivary Gland Neoplasms - metabolism / Salivary Gland Neoplasms - pathology / Salivary glands / Salivary Glands - metabolism / Salivary Glands - pathology / Salivary Proteins and Peptides - genetics / Salivary Proteins and Peptides - metabolism / Science / Science (multidisciplinary) / Transcription factors / Translocation, Genetic