Protein arginine methyltransferase 6-dependent gene expression and splicing: Association with breast cancer outcomes

Dowhan, Dennis H., Harrison, Matthew J., Eriksson, Natalie A., Bailey, Peter, Pearen, Michael A, Fuller, Peter J., Funder, John W., Simpson, Evan R., Leedman, Peter J., Tilley, Wayne D., Brown, Melissa A., Clarke, Christine L. and Muscat, George E. O. (2012) Protein arginine methyltransferase 6-dependent gene expression and splicing: Association with breast cancer outcomes. Endocrine-Related Cancer, 19 4: 509-526. doi:10.1530/ERC-12-0100


Author Dowhan, Dennis H.
Harrison, Matthew J.
Eriksson, Natalie A.
Bailey, Peter
Pearen, Michael A
Fuller, Peter J.
Funder, John W.
Simpson, Evan R.
Leedman, Peter J.
Tilley, Wayne D.
Brown, Melissa A.
Clarke, Christine L.
Muscat, George E. O.
Title Protein arginine methyltransferase 6-dependent gene expression and splicing: Association with breast cancer outcomes
Journal name Endocrine-Related Cancer   Check publisher's open access policy
ISSN 1351-0088
1479-6821
Publication date 2012-08-01
Sub-type Article (original research)
DOI 10.1530/ERC-12-0100
Volume 19
Issue 4
Start page 509
End page 526
Total pages 18
Place of publication Bristol, United Kingdom
Publisher BioScientifica
Collection year 2013
Language eng
Formatted abstract
Protein arginine methyltransferase-6 (PRMT6) regulates steroid-dependent transcription and alternative splicing and is implicated in endocrine system development and function, cell death, cell cycle, gene expression and cancer. Despite its role in these processes, little is known about its function and cellular targets in breast cancer. To identify novel gene targets regulated by PRMT6 in breast cancer cells, we used a combination of small interfering RNA and exon-specific microarray profiling in vitro coupled to in vivo validation in normal breast and primary human breast tumours. This approach, which allows the examination of genome-wide changes in individual exon usage and total transcript levels, demonstrated that PRMT6 knockdown significantly affected i) the transcription of 159 genes and ii) alternate splicing of 449 genes. The PRMT6-dependent transcriptional and alternative splicing targets identified in vitro were validated in human breast tumours. Using the list of genes differentially expressed between normal and PRMT6 knockdown cells, we generated a PRMT6-dependent gene expression signature that provides an indication of PRMT6 dysfunction in breast cancer cells. Interrogation of several well-studied breast cancer microarray expression datasets with the PRMT6 gene expression signature demonstrated that PRMT6 dysfunction is associated with better overall relapse-free and distant metastasis-free survival in the oestrogen receptor (ER (ESR1)) breast cancer subgroup. These results suggest that dysregulation of PRMT6-dependent transcription and alternative splicing may be involved in breast cancer pathophysiology and the molecular consequences identifying a unique and informative biomarker profile.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online before print June 6, 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
 
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Created: Thu, 02 Aug 2012, 15:34:00 EST by Susan Allen on behalf of Institute for Molecular Bioscience