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¹ Division of Gastroenterological Surgery, and
² Division of Breast and Endocrine Surgery, Department of Surgery, St. Marianna University School of Medicine, Kawasaki, 216-8511 Japan
³ Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Australia

Adenomatous polyposis coli (APC), whose mutation causes colorectal cancers, is a key player in the Wnt signaling pathway. While the role of APC in inhibition of β-catenin/LEF1-dependent activation of transformation-inducing genes has been intensively studied and well established, regulation of APC expression at the protein level is only partially understood. Here we report that APC is up-regulated by EDD, the mammalian orthologue of Drosophila melanogaster "hyperplastic discs" gene (hyd) that is considered to be a putative tumor suppressor. Screening of APC immunocomplexes by mass spectrometry identified EDD as a putative APC-interacting protein. Exogenously expressed and endogenous APC interacted with EDD in vivo. Indirect immunofluorescent analyses demonstrated that APC and EDD co-localized in the cytoplasm of the cell. Over-expression of EDD enhanced the protein expression level of APC and its binding partner Axin, resulting in inhibition of Wnt signaling downstream of β-catenin. Conversely, siRNA knock-down of EDD down-regulated APC at the protein level without altering its mRNA level, causing enhanced protein expression of β-catenin. Thus, through protein–protein interaction, EDD stabilizes APC and up-regulates APC's function to inhibit β-catenin, suggesting that EDD could act as a colorectal tumor suppressor.

^* Correspondence: E-mail: to{at}marianna-u.ac.jp