Department of Basic Sciences, The Commonwealth Medical College, 525 Pine Street, Scranton, PA 18509, USA.
J Cancer. 2013 Jul 18;4(6):491-501. doi: 10.7150/jca.6582. Print 2013.
Deregulated WNT/catenin pathway, usually resulting from mutations in the adenomatous polyposis coli and beta-catenin genes, drives colorectal tumorigenesis. Dietary fiber has been shown to have a protective role against colorectal cancer (CRC). We have previously demonstrated that the histone deacetylase inhibitor (HDACi) butyrate, a fermentation product of dietary fiber, induces WNT/catenin hyperactivation, which promotes CRC cell apoptosis. Therefore, the ability of butyrate to induce WNT hyperactivation and thus promote CRC cell apoptosis may in part explain the preventive function of fiber against CRC. The association between beta-catenin and the transcriptional coactivator p300 may influence WNT/catenin signaling and, therefore, colonic cell physiology. p300 functions as a histone acetylase (HAT); therefore, the modulation of WNT/catenin activity by p300 may influence the ability of the HDACi butyrate to hyperinduce WNT signaling and apoptosis in CRC cells. Our findings indicate that p300 affects the hyperinduction of WNT activity by butyrate. Knockdown of p300 levels represses butyrate-mediated WNT/catenin activity; but still allows for butyrate-mediated apoptosis. Overexpression of p300 stimulates basal and butyrate-induced WNT signaling in some, but not all, CRC cell lines. We also evaluate the role of p300 in therapeutic approaches that target CBP. The small molecule ICG-001, in clinical trial, is a specific inhibitor of CBP-mediated WNT signaling, and previous studies have suggested that p300 is required for the activity of ICG-001. However, we report that ICG-001 maintains full activity against CBP-mediated WNT signaling in p300-deficient cell lines, including the butyrate-resistance line HCT-R. In addition, our findings evaluating combinatorial treatment of ICG-001 and butyrate in HCT-R cells may have important therapeutic implications for the treatment of butyrate-resistant CRCs.
WNT/β-连环蛋白信号通路失调通常是由于腺瘤性结肠息肉病和β-连环蛋白基因突变引起的，驱动结直肠肿瘤的发生。膳食纤维已被证明对结直肠癌（CRC）具有保护作用。我们之前已经证明，组蛋白去乙酰化酶抑制剂（HDACi）丁酸盐是膳食纤维的发酵产物，可诱导 WNT/β-连环蛋白过度激活，从而促进 CRC 细胞凋亡。因此，丁酸盐诱导 WNT 过度激活并促进 CRC 细胞凋亡的能力可能部分解释了纤维预防 CRC 的功能。β-连环蛋白与转录共激活因子 p300 的关联可能影响 WNT/β-连环蛋白信号转导，从而影响结肠细胞的生理功能。p300 作为组蛋白乙酰转移酶（HAT）发挥作用；因此，p300 对 WNT/β-连环蛋白活性的调节可能会影响 HDACi 丁酸盐在 CRC 细胞中过度诱导 WNT 信号转导和凋亡的能力。我们的研究结果表明，p300 影响丁酸盐对 WNT 活性的过度诱导。p300 水平的敲低抑制丁酸盐介导的 WNT/β-连环蛋白活性；但仍允许丁酸盐介导的细胞凋亡。在一些但不是所有的 CRC 细胞系中，过表达 p300 可刺激基础和丁酸盐诱导的 WNT 信号。我们还评估了 p300 在针对 CBP 的治疗方法中的作用。处于临床试验阶段的小分子 ICG-001 是 CBP 介导的 WNT 信号的特异性抑制剂，先前的研究表明 p300 是 ICG-001 活性所必需的。然而，我们报告 ICG-001 在包括丁酸盐耐药系 HCT-R 在内的 p300 缺陷细胞系中对 CBP 介导的 WNT 信号仍具有完全活性。此外，我们在 HCT-R 细胞中评估 ICG-001 和丁酸盐联合治疗的发现可能对治疗丁酸盐耐药性 CRC 具有重要的治疗意义。
