The activation of beta-catenin by Wnt signaling mediates the effects of histone deacetylase inhibitors
The activation of beta-catenin by Wnt signaling mediates the effects of histone deacetylase inhibitors
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DOI：
10.1016/j.yexcr.2007.02.008
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发表时间：
2007-05-01
影响因子：
3.7
通讯作者：
Sartorelli, Alan C.
中科院分区：
文献类型：
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作者：
Bordonaro, Michael;Lazarova, Darina L.;Sartorelli, Alan C.
大多数结直肠癌(CRC)表现出结构性活跃的WRIT信号。我们已报道：(A)组蛋白脱乙酰酶抑制剂(HDACi)；(2)丁酸钠(NAB)对体外培养的大肠癌细胞规范的WRIT转录活性有调节作用；(B)在经NAB处理的10株大肠癌细胞系中，WRIT转录活性的增加与细胞凋亡水平之间存在线性关系。在这里，我们报告了结构上不同的HDAC调节CRC细胞中的WRIT信号，参与这一作用的一个机制是增加β-连环蛋白，该蛋白在Ser-37和Thr-41残基上被去磷酸化。HDACis处理的CRC细胞中活性(Ser-37和Thr-41去磷酸化)β-catenin的增加是在配体水平启动的，抑制这种增加会抑制WRIT信号转导，降低细胞凋亡水平。与对凋亡敏感的亲本细胞相比，对HDACis的凋亡效应产生抵抗的CRC细胞表现出更低的活性β-连环蛋白水平，这种抵抗可以通过增加活性β-连环蛋白的水平而被逆转。HDACi耐药细胞和HDACi敏感细胞之间的比较研究结果表明，HDACis的非组蛋白靶点介导了对WRIT信号和细胞凋亡的影响。(C)2007 Elsevier Inc.保留所有权利。
Most colorectal carcinomas (CRCs) exhibit constitutively active Writ signaling. We have reported that (a) the histone deacetylase inhibitor (HDACi)(2) sodium butyrate (NaB) modulates the canonical Writ transcriptional activity of CRC cells in vitro and (b) a linear relationship exists between the increase in Writ transcriptional activity and the levels of apoptosis in ten CRC cell lines treated with NaB. Herein we report that structurally different HDACis modulate Writ signaling in CRC cells and a mechanism involved in this action is an increase in beta-catenin that is dephosphorylated at Ser-37 and Thr-41 residues. The increase of active (Ser-37 and Thr-41 dephosphorylated) beta-catenin in CRC cells treated with HDACis is initiated at the ligand level and the inhibition of this increase suppresses Writ signaling and lowers the levels of apoptosis. CRC cells that develop resistance to the apoptotic effects of HDACis exhibit lower levels of active beta-catenin compared to apoptosis-sensitive parental cells and this resistance is reversed by increasing the levels of active beta-catenin. Results from comparative studies between HDACi-resistant and HDACi-sensitive cells suggest that non-histone targets of HDACis mediate the effects on Writ signaling and apoptosis. (c) 2007 Elsevier Inc. All rights reserved.