Bcl-3 promotes Wnt signaling by maintaining the acetylation of ß-catenin at lysine 49 in colorectal cancer.
Signal Transduct Target Ther
; 5(1): 52, 2020 05 01.
Article
em En
| MEDLINE
| ID: mdl-32355204
ABSTRACT
Wnt/ß-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/ß-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/ß-catenin signaling. Moreover, our data show that Bcl-3 is a crucial component of Wnt/ß-catenin signaling and is essential for ß-catenin transcriptional activity in CRC cells. Interestingly, Wnt3a increases the level and nuclear translocation of Bcl-3, which binds directly to ß-catenin and enhances the acetylation of ß-catenin at lysine 49 (Ac-K49-ß-catenin) and transcriptional activity. Bcl-3 depletion decreases the Ac-K49-ß-catenin level by increasing the level of histone deacetylase 1 to remove acetyl groups from ß-catenin, thus interrupting Wnt/ß-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-ß-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-ß-catenin, which serves as a promising therapeutic target for CRC.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
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Beta Catenina
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Via de Sinalização Wnt
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Proteína 3 do Linfoma de Células B
Limite:
Female
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Humans
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Male
Idioma:
En
Revista:
Signal Transduct Target Ther
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China