ILKAP Promotes the Metastasis of Hepatocellular Carcinoma Cells by Inhibiting β‐Catenin Degradation and Enhancing the WNT Signaling Pathway

Abstract The incidence of Hepatocellular carcinoma (HCC) and HCC‐related deaths have remarkably increased over the recent decades. It has been reported that β‐catenin activation can be frequently observed in HCC cases. This study identified the integrin‐linked kinase‐associated phosphatase (ILKAP) as a novel β‐catenin‐interacting protein. ILKAP is localized both in the nucleus and cytoplasm and regulates the WNT pathway in different ways. First, it is demonstrated that ILKAP activates the WNT pathway in HCC cells by increasing the protein level of β‐catenin and other proteins associated with the WNT signaling, such as c‐Myc and CyclinD1. Next, it is shown that ILKAP promotes the metastasis of HCC both in vitro and in vivo in a zebrafish xenograft model. It is also found that ILKAP dephosphorylates the GSK3β and CK1, contributing to the reduced ubiquitination of β‐catenin. Furthermore, it is identified that ILKAP functions by mediating binding between TCF4 and β‐catenin to enhance expression of WNT target genes. Taken together, the study demonstrates a critical function of ILKAP in metastasis of HCC, since ILKAP is crucial for the activation of the WNT pathway via stabilization of β‐catenin and increased binding between TCF4 and β‐catenin.