title: Cohesin Rad21 mediates loss of heterozygosity and is upregulated via Wnt promoting transcriptional dysregulation in gastrointestinal tumors.
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.
authors.affiliation: 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.
authors.forename: Huiling
authors.initials: H
authors.lastname: Xu
authors.affiliation: Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre (PMCC), East Melbourne, VIC 3002, Australia.
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Pathology Department, PMCC, East Melbourne, VIC 3002, Australia; Victorian Cancer Biobank, Carlton, VIC 3053, Australia.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Deb
authors.affiliation: John Curtin School of Medical Research, The Australian National University, Acton, ACT 2601, Australia.
authors.forename: Danny
authors.initials: D
authors.lastname: Rangasamy
authors.affiliation: 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.
authors.forename: Markus
authors.initials: M
authors.lastname: Germann
authors.affiliation: 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.
authors.forename: Jordane
authors.initials: J
authors.lastname: Malaterre
authors.affiliation: Differentiation and Transcription Laboratory, Peter MacCallum Cancer Centre (PMCC), East Melbourne, VIC 3002, Australia.
authors.forename: Noreen C
authors.initials: NC
authors.lastname: Eder
authors.affiliation: Prince of Wales Clinical School, University of New South Wales (UNSW), Sydney, NSW 2052, Australia.
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Ward
authors.affiliation: School of Medical Sciences, UNSW, Sydney, NSW 2052, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Hawkins
authors.affiliation: Cancer Therapeutics Program, Cancer Research Division, PMCC, East Melbourne, VIC 3002, Australia.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tothill
authors.affiliation: John Curtin School of Medical Research, The Australian National University, Acton, ACT 2601, Australia.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Colorectal Surgery, Oxford University Hospitals, Oxford Cancer Centre, Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Mortensen
authors.affiliation: Department of Pathology, The University of Melbourne, Parkville, VIC 3000, Australia; Pathology Department, PMCC, East Melbourne, VIC 3002, Australia.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fox
authors.affiliation: University of Sydney and North Coast Cancer Institute, Lismore, NSW 2480, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McKay
authors.affiliation: 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.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ramsay
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism; D053687:Adult Stem Cells / Q000502:physiology; D000818:Animals; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D043171:Chromosomal Instability; D003106:Colon / Q000473:pathology; D004249:DNA Damage; D004268:DNA-Binding Proteins; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057895:Haploinsufficiency; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*; D018626:Retroelements / Q000235:genetics; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; C429022:RAD21 protein, human; D018626:Retroelements