Bcl-3 promotes Wnt signaling by maintaining the acetylation of β-catenin at lysine 49 in colorectal cancer

Abstract

Wnt/beta -catenin signaling plays a critical role in colorectal cancer (CRC) tumorigenesis and the homeostasis of colorectal cancer stem cells (CSCs), but its molecular mechanism remains unclear. B-cell lymphoma 3 (Bcl-3), a member of the I kappa B family, is overexpressed in CRC and promotes tumorigenicity. Here, we report a novel function of Bcl-3 in maintaining colorectal CSC homeostasis by activating Wnt/beta -catenin signaling. Silencing Bcl-3 suppresses the self-renewal capacity of colorectal CSCs and sensitizes CRC cells to chemotherapeutic drugs through a decrease in Wnt/beta -catenin signaling. Moreover, our data show that Bcl-3 is a crucial component of Wnt/beta -catenin signaling and is essential for beta -catenin transcriptional activity in CRC cells. Interestingly, Wnt3a increases the level and nuclear translocation of Bcl-3, which binds directly to beta -catenin and enhances the acetylation of beta -catenin at lysine 49 (Ac-K49-beta -catenin) and transcriptional activity. Bcl-3 depletion decreases the Ac-K49-beta -catenin level by increasing the level of histone deacetylase 1 to remove acetyl groups from beta -catenin, thus interrupting Wnt/beta -catenin activity. In CRC clinical specimens, Bcl-3 expression negatively correlates with the overall survival of CRC patients. A significantly positive correlation was found between the expression of Bcl-3 and Ac-K49-beta -catenin. Collectively, our data reveal that Bcl-3 plays a crucial role in CRC chemoresistance and colorectal CSC maintenance via its modulation of the Ac-K49-beta -catenin, which serves as a promising therapeutic target for CRC.