Cohesin Rad21 Mediates Loss of Heterozygosity and Is Upregulated via Wnt Promoting Transcriptional Dysregulation in Gastrointestinal Tumors
Date
2014
Authors
Xu, Huiling
Yan, Yuqian
Deb, Siddhartha
Rangasamy, Danny
Germann, Markus
Malaterre, Jordane
Eder, Noreen
Ward, Robyn
Hawkins, Nicholas
Tothill, Richard
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Elsevier Inc.
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. Rad21 holds the cohesin complex together as part of its role in chromosome partitioning and DNA repair. Xu etal. 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.
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Cell Reports
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Journal article
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2037-12-31
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