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 nuclear retention remains largely unknown.

In a recent paper from Prof. Tianhua Zhou’s lab reported that Twa1/Gid8 is a key nuclear retention factor for β-catenin during Wnt signaling and colorectal carcinogenesis. Twa1, also known as Gid8, was initially described in the hunt for the proteins that can interact with Ran binding protein M, but its biological function remains largely unclear. Using a comprehensive approach, they found that Twa1 is not only significantly upregulated in human CRC tissues, but also that this correlates with a poor prognosis for CRC patients. In the absence of Wnt, Twa1 exists together with β-catenin in the Axin complex and undergoes ubiquitination and degradation. In response to Wnt signaling, Twa1 directly binds to β-catenin and promotes its nuclear retention. More importantly, they exemplified the functions of Twa1 by showing its requirement for the dorsal development of zebrafish embryos and for the growth of CRC cells in a xenograft model. Although Twa1 associates with β-catenin in the nucleus, it does not interact with either TCF4 or Wnt-responsive elements, suggesting a chromatin-independent retention mechanism that is indispensible for the Wnt transcriptional program. This study identifies Twa1 as a previously undescribed regulator of the Wnt pathway for promoting colorectal tumorigenesis by facilitating β-catenin nuclear retention, which not only extends our current understanding of Wnt signaling, but also provides a potential therapeutic target for CRC patients.

This work was published in Cell Research entitled “Twa1/Gid8 is a β-catenin nuclear retention factor in Wnt signaling and colorectal tumorigenesis” on August 22th, 2017. This study was supported by the National Natural Science Foundation of China, the Ministry of Science and Technology of China, Department of Science and Technology of Zhejiang Province and Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents.