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

被引：164

作者：

Haller, Florian ^{[1
]}

Bieg, Matthias ^{[2
,3
,4
]}

Will, Rainer ^{[5
]}

Koerner, Cindy ^{[6
]}

Weichenhan, Dieter ^{[7
]}

Bott, Alexander ^{[6
]}

Ishaque, Naveed ^{[2
,3
,4
]}

Lutsik, Pavlo ^{[7
]}

Moskalev, Evgeny A. ^{[1
]}

Mueller, Sarina K. ^{[8
]}

Baehr, Marion ^{[7
]}

Woerner, Angelika ^{[6
]}

Kaiser, Birgit ^{[5
]}

Scherl, Claudia ^{[8
]}

Haderlein, Marlen ^{[9
]}

Kleinheinz, Kortine ^{[10
]}

Fietkau, Rainer ^{[9
]}

Iro, Heinrich ^{[8
]}

Eils, Roland ^{[2
,3
,4
,11
,12
]}

Hartmann, Arndt ^{[1
]}

Plass, Christoph ^{[7
]}

Wiemann, Stefan ^{[5
,6
]}

Agaimy, Abbas ^{[1
]}

机构：

[1] Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Inst Pathol, Krankenhausstr 8-10, D-91054 Erlangen, Germany

[2] Berlin Inst Hlth, Ctr Digital Hlth, Kapelle Ufer 2, D-10117 Berlin, Germany

[3] Charite Univ Med Berlin, Kapelle Ufer 2, D-10117 Berlin, Germany

[4] Heidelberg Ctr Personalized Oncol DKFZ HIPO, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[5] German Canc Res Ctr, Genom & Prote Core Facil, Neuenheimer Feld 580, D-69120 Heidelberg, Germany

[6] German Canc Res Ctr, Div Mol Genome Anal, Neuenheimer Feld 580, D-69120 Heidelberg, Germany

[7] German Canc Res Ctr, Div Canc Epigen, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[8] Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Dept Otorhinolaryngol Head & Neck Surg, Waldstr 1, D-91054 Erlangen, Germany

[9] Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Dept Radiat Therapy, Univ Str 27, D-91054 Erlangen, Germany

[10] German Canc Res Ctr, Div Theoret Bioinformat B080, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[11] Univ Hosp Heidelberg, Hlth Data Sci Unit, Neuenheimer Feld 267, D-69120 Heidelberg, Germany

[12] Heidelberg Univ, German Ctr Lung Res, Translat Lung Res Ctr Heidelberg, Neuenheimer Feld 156, D-69120 Heidelberg, Germany

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

ORPHAN NUCLEAR RECEPTOR; GENE; EXPRESSION; ALIGNMENT; CANCER; TUMORS; FUSION; HEAD; NOR1; MYB;

D O I：

10.1038/s41467-018-08069-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13

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