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

Huiling Xu; Yuqian Yan; Siddhartha Deb; Danny Rangasamy; Markus Germann; Jordane Malaterre; Noreen C Eder; Robyn L Ward; Nicholas J Hawkins; Richard W Tothill; Long Chen; Neil J Mortensen; Stephen B Fox; Michael J McKay; Robert G Ramsay

doi:10.1016/j.celrep.2014.10.059

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

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

Authors

Affiliations

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: [email protected].

PMID: 25464844
DOI: 10.1016/j.celrep.2014.10.059

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenomatous Polyposis Coli / genetics*
Adenomatous Polyposis Coli / metabolism
Adult Stem Cells / physiology
Animals
Cell Cycle Proteins
Cell Proliferation
Chromosomal Instability
Colon / pathology
DNA Damage
DNA-Binding Proteins
Gene Expression
Gene Expression Regulation, Neoplastic
HCT116 Cells
Haploinsufficiency*
Humans
Mice
Mice, Transgenic
Nuclear Proteins / physiology*
Phosphoproteins / physiology*
Retroelements / genetics
Up-Regulation

Substances

Cell Cycle Proteins
DNA-Binding Proteins
Nuclear Proteins
Phosphoproteins
RAD21 protein, human
Retroelements