Abstract
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.
Highlights
The molecular pathogenesis of salivary gland acinic cell carcinoma (AciCC) is poorly understood
The genomic breakpoints within the secretory Ca-binding phosphoprotein (SCPP) gene cluster correlate with high H3K27ac active chromatin marks that are present in both normal parotid gland and AciCC tumor tissues, and we demonstrate significant enhancer activity within the breakpoint region in a functional analysis
There is an increase in active chromatin marks and upregulation of gene expression in AciCC tumor tissues compared to normal parotid gland that is significantly correlated with the NR4A3 transcription factor binding motif
Summary
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 expressed at high levels in the salivary glands and constitute major components of saliva. The genomic breakpoints within the SCPP gene cluster correlate with high H3K27ac active chromatin marks that are present in both normal parotid gland and AciCC tumor tissues, and we demonstrate significant enhancer activity within the breakpoint region in a functional analysis. We show that NR4A3 is and consistently upregulated in AciCCs. There is an increase in active chromatin marks and upregulation of gene expression in AciCC tumor tissues compared to normal parotid gland that is significantly correlated with the NR4A3 transcription factor binding motif. We suggest that NR4A3 upregulation is an early oncogenic event in AciCCs through constitutive stimulation of cell proliferation
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