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

ABSTRACT: Wnt/?-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?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/?-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/?-catenin signaling. Moreover, our data show that Bcl-3 is a crucial component of Wnt/?-catenin signaling and is essential for ?-catenin transcriptional activity in CRC cells. Interestingly, Wnt3a increases the level and nuclear translocation of Bcl-3, which binds directly to ?-catenin and enhances the acetylation of ?-catenin at lysine 49 (Ac-K49-?-catenin) and transcriptional activity. Bcl-3 depletion decreases the Ac-K49-?-catenin level by increasing the level of histone deacetylase 1 to remove acetyl groups from ?-catenin, thus interrupting Wnt/?-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-?-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-?-catenin, which serves as a promising therapeutic target for CRC.

SUBMITTER: Chen X 

PROVIDER: S-EPMC7193563 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature