c-Cbl mediates the degradation of tumorigenic nuclear β-catenin contributing to the heterogeneity in Wnt activity in colorectal tumors

// Moshe Shashar 1 , Jamaica Siwak 1 , Umit Tapan 2 , Shin Yin Lee 2 , Rosana D. Meyer 3 , Paige Parrack 1 , Josenia Tan 3 , Fatemeh Khatami 1 , Jean Francis 1 , Qing Zhao 3 , Kevan Hartshorn 2 , Vijaya B. Kolachalama 4,5 , Nader Rahimi 3 and Vipul Chitalia 1,4 1 Department of Medicine, Boston University School of Medicine, Boston, MA, USA 2 Department of Medicine, Hematology-Oncology Section, Boston University School of Medicine, Boston, MA, USA 3 Department of Pathology, Boston University School of Medicine, Boston, MA, USA 4 Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA 5 Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA Correspondence to: Vipul Chitalia, email: // Keywords : colorectal cancer, Cbl, Wnt Received : June 16, 2016 Accepted : August 21, 2016 Published : September 20, 2016 Abstract Despite the loss of Adenomatous Polyposis Coli ( APC ) in a majority of colorectal cancers (CRC), not all CRCs bear hallmarks of Wnt activation, such as nuclear β-catenin. This underscores the presence of other Wnt regulators that are important to define, given the pathogenic and prognostic roles of nuclear β-catenin in human CRC. Herein, we investigated the effect of Casitas B-lineage lymphoma (c-Cbl) on nuclear β-catenin, which is an oncoprotein upregulated in CRC due to loss-of-function APC or gain-of-function CTNNB1 mutations. Despite mechanistic rationale and recent discoveries of c-Cbl’s mutations in solid tumors, little is known about its functional importance in CRC. Our study in a cohort of human CRC patients demonstrated an inverse correlation between nuclear β-catenin and c-Cbl. Further investigation showed that the loss of c-Cbl activity significantly enhanced nuclear β-catenin and CRC tumor growth in cell culture and a mouse xenograft model. c-Cbl interacted with and downregulated β-catenin in a manner that was independent of CTNNB1 or APC mutation status. This study demonstrates a previously unrecognized function of c-Cbl as a negative regulator of CRC.