Bcl-3 promotes Wnt signaling by maintaining the acetylation of β-catenin at lysine 49 in colorectal cancer
Bcl-3 promotes Wnt signaling by maintaining the acetylation of β-catenin at lysine 49 in colorectal cancer
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Bcl-3 通过维持结直肠癌中 β-连环蛋白 49 位赖氨酸的乙酰化来促进 Wnt 信号传导
DOI：
10.1038/s41392-020-0138-6
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发表时间：
2020-05-01
影响因子：
39.3
通讯作者：
Zhang, Xiaoren
中科院分区：
文献类型：
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作者：
Chen, Xi;Wang, Chen;Zhang, Xiaoren
Wnt/ β -catenin信号在结直肠癌（CRC）的肿瘤发生和结直肠癌干细胞（CSCs）的稳态中起关键作用，但其分子机制尚不清楚。B细胞淋巴瘤3 （Bcl-3）是I κ B家族的一员，在结直肠癌中过表达并促进肿瘤发生。在这里，我们报道了Bcl-3通过激活Wnt/ β -catenin信号通路来维持结直肠CSC稳态的新功能。沉默Bcl-3抑制结直肠癌csc的自我更新能力，并通过减少Wnt/ β -catenin信号通路使结直肠癌细胞对化疗药物敏感。此外，我们的数据显示Bcl-3是Wnt/ β -catenin信号传导的重要组成部分，对CRC细胞中β -catenin转录活性至关重要。有趣的是，Wnt3a增加了Bcl-3的水平和核易位，Bcl-3直接与β -catenin结合，增强β -catenin在赖氨酸49处的乙酰化（ac - k49 - β -catenin）和转录活性。Bcl-3缺失通过增加组蛋白去乙酰化酶1的水平来降低ac - k49 - β -catenin水平，从而破坏Wnt/ β -catenin活性。在结直肠癌临床标本中，Bcl-3的表达与结直肠癌患者的总生存率呈负相关。Bcl-3与ac - k49 - β -catenin的表达呈显著正相关。总的来说，我们的数据表明Bcl-3通过调节ac - k49 - β -catenin在结直肠癌化疗耐药和结直肠癌CSC维持中起着至关重要的作用，而ac - k49 - β -catenin是结直肠癌的一个有希望的治疗靶点。
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.