Abstract 108: Functional characterization of WAC, a candidate tumor suppressor gene in colorectal cancer

Abstract

Abstract Broadening our understanding of the genetic basis of cancer will facilitate construction of relevant pre-clinical models and provide novel targets for drug development. To identify genes that contribute to the initiation or progression of colorectal cancer (CRC) when mutated or dysregulated, we recently conducted a set of forward genetic screens using transposon insertional mutagenesis to drive intestinal tumor formation in mice. These studies were designed to identify novel cancer genes that function in a wildtype genetic context or cooperate with known predisposing alleles (ApcMin/+ or Trp53R270H/+). Over 150 genes were identified, including several known to be important in human CRC (eg. APC, PTEN, and FBXW7) and many novel candidate cancer genes. WW domain containing adaptor with coiled-coil (WAC), is a gene not previously associated with cancer that was identified in all three screens. While the function of WAC is incompletely understood, previous reports indicate that the WAC protein participates in multiple cellular processes, including golgi biogenesis, modulation of gene expression, and induction of p21CIP1 expression and cell cycle arrest in response to DNA damage. In this study, we evaluated the role of WAC in cellular transformation by depleting WAC in mouse colonic epithelial cells conditionally immortalized by expression of a temperature sensitive SV40 large T antigen. In this model, loss of WAC expression increased anchorage-independent growth of colonic epithelial cells in cooperation with mutant APC. In human CRC samples, resequencing the WAC gene identified non-silent mutations in 2 of 74 samples. Further, CRC-associated WAC mutants were found to be functionally deficient in induction of p21CIP1 in a zebrafish embryo model. These data are consistent with the model that WAC functions as a tumor suppressor in the colonic epithelium. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 108. doi:1538-7445.AM2012-108