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Mol Cancer Res. 2014 Dec;12(12):1818-28. doi: 10.1158/1541-7786.MCR-14-0167. Epub 2014 Aug 4.

Metastasis-associated protein ribosomal RNA processing 1 homolog B (RRP1B) modulates metastasis through regulation of histone methylation.

Author information

1
Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland.
2
Genome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland.
3
Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland. crawforn@mail.nih.gov.

Abstract

Overexpression of ribosomal RNA processing 1 homolog B (RRP1B) induces a transcriptional profile that accurately predicts patient outcome in breast cancer. However, the mechanism by which RRP1B modulates transcription is unclear. Here, the chromatin-binding properties of RRP1B were examined to define how it regulates metastasis-associated transcription. To identify genome-wide RRP1B-binding sites, high-throughput ChIP-seq was performed in the human breast cancer cell line MDA-MB-231 and HeLa cells using antibodies against endogenous RRP1B. Global changes in repressive marks such as histone H3 lysine 9 trimethylation (H3K9me3) were also examined by ChIP-seq. Analysis of these samples identified 339 binding regions in MDA-MB-231 cells and 689 RRP1B-binding regions in HeLa cells. Among these, 136 regions were common to both cell lines. Gene expression analyses of these RRP1B-binding regions revealed that transcriptional repression is the primary result of RRP1B binding to chromatin. ChIP-reChIP assays demonstrated that RRP1B co-occupies loci with decreased gene expression with the heterochromatin-associated proteins, tripartite motif-containing protein 28 (TRIM28/KAP1), and heterochromatin protein 1-α (CBX5/HP1α). RRP1B occupancy at these loci was also associated with higher H3K9me3 levels, indicative of heterochromatinization mediated by the TRIM28/HP1α complex. In addition, RRP1B upregulation, which is associated with metastasis suppression, induced global changes in histone methylation.

IMPLICATIONS:

RRP1B, a breast cancer metastasis suppressor, regulates gene expression through heterochromatinization and transcriptional repression, which helps our understanding of mechanisms that drive prognostic gene expression in human breast cancer.

PMID:
25092915
PMCID:
PMC4272606
DOI:
10.1158/1541-7786.MCR-14-0167
[Indexed for MEDLINE]
Free PMC Article

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