Colorectal Cancer (CRC) is a genetic disease in which progression is driven by the accumulation of mutations or epigenetic alterations in oncogenes and tumor suppressor genes. Despite significant progress, additional work remains to identify the heterogeneous genetic events that drive this process and to understand how they cooperate in disease progression. We have identified WW domain containing adaptor with coiled-coil (WAC) as a candidate tumor suppressor gene in colorectal cancer, based on its loss of function in three forward genetic screens for intestinal tumors in mice. Although little is know about the function of WAC, it has been shown that the WAC protein functions as an adaptor in multiple protein complexes in diverse biological processes, including transcription-coupled histone modification and golgi biogenesis. We hypothesize that disruption of WAC contributes to human colorectal cancer based on preliminary data showing that depletion of WAC in conditionally immortalized colonic epithelial cells leads to increased anchorage-independent growth in vitro. Additionally, sequencing the WAC gene in a set of 74 human colorectal cancer samples identified non- silent mutations in WAC at a frequency of 2.7%. In future work, we propose to define the mechanism by which decreased WAC expression contributes to anchorage-independence, and to characterize the functional deficits and transforming capacity of cancer-associated WAC mutants. Finally, we aim to describe the full transcriptional program regulated by the WAC complex under conditions of anchorage-independence, in order to describe a novel tumor suppressor pathway whose disruption may facilitate progression of colorectal cancer.
Relevance of this research to public health Colorectal cancer is the third-leading cause of cancer-related mortality in the United States and a significant publi health problem. The proposed work will expand our understanding of the genetic mechanisms of colorectal cancer. This understanding will contribute to the development of better pre-clinical models that faithfully recapitulate the human disease. Additionally, discovering and validating new genetic drivers will provide novel targets for drug development to improve treatment options and outcomes in colorectal cancer.
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