FLYWCH1, a Novel Suppressor of Nuclear β-Catenin, Regulates Migration and Morphology in Colorectal Cancer.

Wnt/β-catenin signaling plays a critical role during development of both normal and malignant colorectal cancer tissues. Phosphorylation of β-catenin protein alters its trafficking and function. Such conventional allosteric regulation usually involves a highly specialized set of molecular interactions, which may specifically turn on a particular cell phenotype. This study identifies a novel transcription modulator with an FLYWCH/Zn-finger DNA-binding domain, called "FLYWCH1." Using a modified yeast-2-hybrid based Ras-Recruitment system, it is demonstrated that FLYWCH1 directly binds to unphosphorylated (nuclear) β-catenin efficiently suppressing the transcriptional activity of Wnt/β-catenin signaling that cannot be rescued by TCF4. FLYWCH1 rearranges the transcriptional activity of β-catenin/TCF4 to selectively block the expression of specific downstream genes associated with colorectal cancer cell migration and morphology, including ZEB1, EPHA4, and E-cadherin. Accordingly, overexpression of FLYWCH1 reduces cell motility and increases cell attachment. The expression of FLYWCH1 negatively correlates with the expression level of ZEB1 and EPHA4 in normal versus primary and metastatic colorectal cancer tissues in patients. Thus, FLYWCH1 antagonizes β-catenin/TCF4 signaling during cell polarity/migration in colorectal cancer. Implications: This study uncovers a new molecular mechanism by which FLYWCH1 with a possible tumor suppressive role represses β-catenin-induced ZEB1 and increases cadherin-mediated cell attachment preventing colorectal cancer metastasis. Mol Cancer Res; 1-14. ©2018 AACR.