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Cell Rep. 2014 Dec 11;9(5):1781-1797. doi: 10.1016/j.celrep.2014.10.059. Epub 2014 Nov 20.

Cohesin Rad21 mediates loss of heterozygosity and is upregulated via Wnt promoting transcriptional dysregulation in gastrointestinal tumors.

Author information

1
Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre (PMCC), East Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3000, Australia; Department of Pathology, The University of Melbourne, Parkville, VIC 3000, Australia.
2
Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre (PMCC), East Melbourne, VIC 3002, Australia.
3
Pathology Department, PMCC, East Melbourne, VIC 3002, Australia; Victorian Cancer Biobank, Carlton, VIC 3053, Australia.
4
John Curtin School of Medical Research, The Australian National University, Acton, ACT 2601, Australia.
5
Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre (PMCC), East Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3000, Australia.
6
Prince of Wales Clinical School, University of New South Wales (UNSW), Sydney, NSW 2052, Australia.
7
School of Medical Sciences, UNSW, Sydney, NSW 2052, Australia.
8
Cancer Therapeutics Program, Cancer Research Division, PMCC, East Melbourne, VIC 3002, Australia.
9
Department of Colorectal Surgery, Oxford University Hospitals, Oxford Cancer Centre, Churchill Hospital, Oxford OX3 7LJ, UK.
10
Department of Pathology, The University of Melbourne, Parkville, VIC 3000, Australia; Pathology Department, PMCC, East Melbourne, VIC 3002, Australia.
11
University of Sydney and North Coast Cancer Institute, Lismore, NSW 2480, Australia.
12
Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre (PMCC), East Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3000, Australia. Electronic address: rob.ramsay@petermac.org.

Abstract

Loss of heterozygosity (LOH) of the adenomatous polyposis coli (APC) gene triggers a series of molecular events leading to intestinal adenomagenesis. Haploinsufficiency of the cohesin Rad21 influences multiple initiating events in colorectal cancer (CRC). We identify Rad21 as a gatekeeper of LOH and a β-catenin target gene and provide evidence that Wnt pathway activation drives RAD21 expression in human CRC. Genome-wide analyses identified Rad21 as a key transcriptional regulator of critical CRC genes and long interspersed element (LINE-1 or L1) retrotransposons. Elevated RAD21 expression tracks with reactivation of L1 expression in human sporadic CRC, implicating cohesin-mediated L1 expression in global genomic instability and gene dysregulation in cancer.

PMID:
25464844
DOI:
10.1016/j.celrep.2014.10.059
[Indexed for MEDLINE]
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