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
Affiliations
Huiling Xu
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
Yuqian Yan
Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre (PMCC), East Melbourne, VIC 3002, Australia
Siddhartha Deb
Pathology Department, PMCC, East Melbourne, VIC 3002, Australia; Victorian Cancer Biobank, Carlton, VIC 3053, Australia
Danny Rangasamy
John Curtin School of Medical Research, The Australian National University, Acton, ACT 2601, Australia
Markus Germann
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
Jordane Malaterre
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
Noreen C. Eder
Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre (PMCC), East Melbourne, VIC 3002, Australia
Robyn L. Ward
Prince of Wales Clinical School, University of New South Wales (UNSW), Sydney, NSW 2052, Australia
Nicholas J. Hawkins
School of Medical Sciences, UNSW, Sydney, NSW 2052, Australia
Richard W. Tothill
Cancer Therapeutics Program, Cancer Research Division, PMCC, East Melbourne, VIC 3002, Australia
Long Chen
John Curtin School of Medical Research, The Australian National University, Acton, ACT 2601, Australia
Neil J. Mortensen
Department of Colorectal Surgery, Oxford University Hospitals, Oxford Cancer Centre, Churchill Hospital, Oxford OX3 7LJ, UK
Stephen B. Fox
Department of Pathology, The University of Melbourne, Parkville, VIC 3000, Australia; Pathology Department, PMCC, East Melbourne, VIC 3002, Australia
Michael J. McKay
University of Sydney and North Coast Cancer Institute, Lismore, NSW 2480, Australia
Robert G. Ramsay
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; Corresponding author
Summary: 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. : Rad21 holds the cohesin complex together as part of its role in chromosome partitioning and DNA repair. Xu et al. identify Rad21 as a key mediator of Apc gene heterozygous loss, the event initiating intestinal tumorigenesis. The subsequent activation of the Wnt pathway further induces Rad21, global gene dysregulation, chromosome instability, and pervasive retrotransposon activation.
