CBP Activity Mediates Effects of the Histone Deacetylase Inhibitor Butyrate on WNT Activity and Apoptosis in Colon Cancer Cells.
CBP Activity Mediates Effects of the Histone Deacetylase Inhibitor Butyrate on WNT Activity and Apoptosis in Colon Cancer Cells.
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DOI：
10.7150/jca.6583
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发表时间：
2013
影响因子：
3.9
通讯作者：
Bordonaro M
中科院分区：
文献类型：
--
作者：
Lazarova DL;Chiaro C;Wong T;Drago E;Rainey A;O'Malley S;Bordonaro M
WNT/ β -连环蛋白通路的突变是导致大多数结直肠癌（crc）发生的原因。我们之前已经证明，组蛋白去乙酰化酶抑制剂（HDACis）如丁酸盐（一种膳食纤维的发酵产物）对该信号的过度激活可促进结直肠癌细胞凋亡。β -连环蛋白和转录辅激活因子creb结合蛋白（CBP）之间的关联程度影响WNT/连环蛋白信号传导，从而影响结肠细胞生理学。CBP作为组蛋白乙酰化酶（HAT）发挥作用；因此，我们假设CBP对WNT/catenin活性的调节改变了HDACi丁酸盐在结直肠癌细胞中高诱导WNT信号和凋亡的能力。我们的研究结果表明，CBP影响丁酸盐对WNT活性的高诱导。ICG-001特异性阻断CBP和β -catenin之间的关联，消除了丁酸盐引发的CRC细胞数量增加，具有高水平的WNT/catenin信号。ICG-001和丁酸盐联合治疗CRC细胞对细胞凋亡具有特异性作用。此外，丁酸盐和ICG-001都能抑制结直肠癌细胞的增殖，并具有抑制细胞生长的叠加效应。我们的研究强烈表明，icg -001样药物对丁酸盐/ hdac耐药的CRC细胞有效。因此，icg -001样药物可能是一种重要的治疗选择，用于在hdac存在下表现出WNT活性低倍超激活和凋亡的crc。这项研究的结果可能会导致利用CBP活性调节来促进CRC治疗或化学预防策略的方法。
Mutations in the WNT/beta-catenin pathway are responsible for initiating the majority of colorectal cancers (CRCs). We have previously shown that hyperactivation of this signaling by histone deacetylase inhibitors (HDACis) such as butyrate, a fermentation product of dietary fiber, promotes CRC cell apoptosis. The extent of association between beta-catenin and the transcriptional coactivator CREB-binding protein (CBP) influences WNT/catenin signaling and, therefore, colonic cell physiology. CBP functions as a histone acetylase (HAT); therefore, we hypothesized that the modulation of WNT/catenin activity by CBP modifies the ability of the HDACi butyrate to hyperinduce WNT signaling and apoptosis in CRC cells. Our findings indicate that CBP affects the hyperinduction of WNT activity by butyrate. ICG-001, which specifically blocks association between CBP and beta-catenin, abrogates the butyrate-triggered increase in the number of CRC cells with high levels of WNT/catenin signaling. Combination treatment of CRC cells with ICG-001 and butyrate results in cell type-specific effects on apoptosis. Further, both butyrate and ICG-001 repress CRC cell proliferation, with additive effects in suppressing cell growth. Our study strongly suggests that ICG-001-like agents would be effective against butyrate/HDACi-resistant CRC cells. Therefore, ICG-001-like agents may represent an important therapeutic option for CRCs that exhibit low-fold hyperactivation of WNT activity and apoptosis in the presence of HDACis. The findings generated from this study may lead to approaches that utilize modulation of CBP activity to facilitate CRC therapeutic or chemopreventive strategies.
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影响因子：
11.4
作者：
Hecht, A;Vleminckx, K;Kemler, R
通讯作者：
Kemler, R
DOI：
10.1007/s00432-005-0013-4
发表时间：
2005-10-01
影响因子：
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作者：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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