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.

中文翻译：

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Twa1 / Gid8是Wnt信号传导和结肠直肠肿瘤发生中的β-catenin核保留因子。

Wnt /β-catenin信号的过度激活是人类结直肠癌（CRC）的主要原因之一。Wnt信号的标志是β-catenin的核积累。尽管已经广泛研究了β-catenin核的进出口，但是β-catenin核保留的潜在机制仍然未知。在这里，我们报道Twa1 / Gid8是Wnt信号传导和结直肠癌变过程中β-catenin的关键核保留因子。在没有Wnt的情况下，Twa1与β-catenin一起存在于Axin复合物中，并发生泛素化和降解。在Wnt信号转导后，Twa1易位到细胞核中，在那里它结合并保留β-catenin。Twa1的耗竭减弱了Wnt刺激的基因表达，斑马鱼胚胎的背侧发育以及CRC细胞的异种移植肿瘤的生长。而且，核Twa1在人CRC组织中显着上调，与β-catenin的核蓄积和预后不良有关。因此，我们的结果将Twa1鉴定为Wnt通路的一个先前未描述的调节子，该通路通过促进β-catenin的核保留而促进结直肠肿瘤的发生。