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.
Nat Commun. 2019 Jan 21;10(1):368. doi: 10.1038/s41467-018-08069-x.
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.
唾液腺闰管细胞癌（AciCC）的分子发病机制尚不清楚。4q13 上的分泌钙结合磷蛋白（SCPP）基因簇编码结构相关的磷蛋白，其中一些在唾液腺中特异性高水平表达，构成唾液的主要成分。在这里，我们报告了 AciCC 中经常发生的重排[t(4;9)(q13;q31)]，该重排将 SCPP 基因簇中的活性增强子区域易位到 9q31 上的核受体亚家族 4 组 A 成员 3（NR4A3）的上游区域。我们表明，NR4A3 在 AciCC 中特异性地上调，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。在小鼠唾液腺细胞中过表达 NR4A3 会增加已知的 NR4A3 靶基因的表达，并对细胞增殖具有刺激功能作用。我们得出结论，NR4A3 通过增强子劫持而上调，并在 AciCC 中具有重要的致癌功能。
