Twa1/Gid8 is a β-catenin nuclear retention factor in Wnt signaling and colorectal tumorigenesis

Hyperactivation of Wnt/β-catenin signaling is one of the major causes of human colorectal cancer （CRC）. A hallmark of Wnt signaling is the nuclear accumulation of β-catenin. Although β-catenin nuclear import and export have been widely investigated, the underlying mechanism of β-catenin＇s nuclear retention remains largely unknown. Here, we report that Twa1/Gid8 is a key nuclear retention factor for β-catenin during Wnt signaling and colorectal carcinogenesis. In the absence of Wnt, Twal exists together with/β-catenin in the Axin complex and undergoes ubiquitination and degradation. Upon Wnt signaling, Twal transloeates into the nucleus, where it binds and retains β-catenin. Depletion of Twal attenuates Wnt-stimulated gene expression, dorsal development of zebrafish embryos and xenograft tu- mor growth of CRC cells. Moreover, nuclear Twal is significantly upregulated in human CRC tissues, correlating with the nuclear accumulation of β-catenin and poor prognosis. Thus, our results identify Twal as a previously undescribed regulator of the Wnt pathway for promoting colorectal tumorigenesis by facilitating β-catenin nuclear retention.