Bcl-3 promotes Wnt signaling by maintaining the acetylation of β-catenin at lysine 49 in colorectal cancer
Open Access
- 1 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Signal Transduction and Targeted Therapy
- Vol. 5 (1), 1-12
- https://doi.org/10.1038/s41392-020-0138-6
Abstract
Wnt/β-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 IκB 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/β-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/β-catenin signaling. Moreover, our data show that Bcl-3 is a crucial component of Wnt/β-catenin signaling and is essential for β-catenin transcriptional activity in CRC cells. Interestingly, Wnt3a increases the level and nuclear translocation of Bcl-3, which binds directly to β-catenin and enhances the acetylation of β-catenin at lysine 49 (Ac-K49-β-catenin) and transcriptional activity. Bcl-3 depletion decreases the Ac-K49-β-catenin level by increasing the level of histone deacetylase 1 to remove acetyl groups from β-catenin, thus interrupting Wnt/β-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-β-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-β-catenin, which serves as a promising therapeutic target for CRC.Keywords
Funding Information
- National Natural Science Foundation of China (31570902)
This publication has 47 references indexed in Scilit:
- ROS Production and NF-κB Activation Triggered by RAC1 Facilitate WNT-Driven Intestinal Stem Cell Proliferation and Colorectal Cancer InitiationCell Stem Cell, 2013
- Wnt/β-Catenin Signaling and DiseaseCell, 2012
- Modeling Oncogenic Signaling in Colon Tumors by Multidirectional Analyses of Microarray Data Directed for Maximization of Analytical ReliabilityPLOS ONE, 2010
- Quiescent, Slow-Cycling Stem Cell Populations in Cancer: A Review of the Evidence and Discussion of SignificanceJournal of Oncology, 2010
- Cancer stem cells from colorectal cancer-derived cell linesProceedings of the National Academy of Sciences of the United States of America, 2010
- Adiponectin Inhibits Pro-inflammatory Signaling in Human Macrophages Independent of Interleukin-10Online Journal of Public Health Informatics, 2009
- HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the β-catenin–TCF interactionNature Neuroscience, 2009
- High expression of BCL3 in human myeloma cells is associated with increased proliferation and inferior prognosisEuropean Journal of Haematology, 2009
- PCAF Acetylates β-Catenin and Improves Its StabilityMolecular Biology of the Cell, 2009
- WNT and β-catenin signalling: diseases and therapiesNature Reviews Genetics, 2004