Volume 27, No 12, Dec 2017

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 27 Issue 12, December 2017: 1422-1440   |  Open Access

ORIGINAL ARTICLES

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

Yi Lu^1,2,*, Shanshan Xie^1,*, Wen Zhang^1,*, Cheng Zhang¹, Cheng Gao¹, Qiang Sun¹, Yuqi Cai^1,6, Zhangqi Xu¹, Min Xiao¹, Yanjun Xu³, Xiao Huang⁴, Ximei Wu¹, Wei Liu^1,2, Fudi Wang^1,2, Yibin Kang⁵ and Tianhua Zhou^1,2

¹Department of Cell Biology and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
²Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China
³Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China
⁴Institute of Cellular and Developmental Biology, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
⁵Department of Molecular Biology, Princeton University, Princeton, NJ 08540, USA
⁶Current address: Division of Pulmonary Biology, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA Correspondence: Tianhua Zhou, Tel: +86 571 88208258(tzhou@zju.edu.cn)

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.

10.1038/cr.2017.107

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