Enhancer hijacking activates oncogenic transcription factor NR4A3 in acinic cell carcinomas of the salivary glands.
Acinar Cells
/ metabolism
Animals
Carcinoma, Acinar Cell
/ genetics
Cell Proliferation
Chromatin
/ chemistry
Chromosomes, Human, Pair 4
/ chemistry
Chromosomes, Human, Pair 9
/ chemistry
Cohort Studies
DNA-Binding Proteins
/ genetics
Enhancer Elements, Genetic
Epigenesis, Genetic
Female
Gene Expression Regulation, Neoplastic
Genetic Loci
Humans
Male
Mice
Multigene Family
Primary Cell Culture
Receptors, Steroid
/ genetics
Receptors, Thyroid Hormone
/ genetics
Salivary Gland Neoplasms
/ genetics
Salivary Glands
/ metabolism
Salivary Proteins and Peptides
/ genetics
Translocation, Genetic
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
21 01 2019
21 01 2019
Historique:
received:
08
02
2018
accepted:
12
12
2018
entrez:
22
1
2019
pubmed:
22
1
2019
medline:
6
2
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 30664630
doi: 10.1038/s41467-018-08069-x
pii: 10.1038/s41467-018-08069-x
pmc: PMC6341107
doi:
Substances chimiques
Chromatin
0
DNA-Binding Proteins
0
NR4A3 protein, human
0
Receptors, Steroid
0
Receptors, Thyroid Hormone
0
Salivary Proteins and Peptides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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