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

• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2017,（12）
• 页码范围: 1422-1440
• 页数: 19页
• 语种: 英文
• DOI: 10.1038/cr.2017.107

摘要

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,Twa1 exists together with β-catenin in the Axin complex and undergoes ubiquitination and degradation.Upon Wnt signaling,Twa1 translocates into the nucleus,where it binds and retains β-catenin.Depletion of Twa1 attenuates Wnt-stimulated gene expression,dorsal development of zebrafish embryos and xenograft tumor growth of CRC cells.Moreover,nuclear Twa1 is significantly upregulated in human CRC tissues,correlating with the nuclear accumulation of β-catenin and poor prognosis.Thus,our results identify Twa1 as a previously undescribed regulator of the Wnt pathway for promoting colorectal tumorigenesis by facilitating β-catenin nuclear retention.