DNA methyltransferase inhibitor zebularine induces human cholangiocarcinoma cell death through alteration of DNA methylation status.
DNA methyltransferase inhibitor zebularine induces human cholangiocarcinoma cell death through alteration of DNA methylation status.
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DOI：
10.1371/journal.pone.0120545
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Tanoue A
中科院分区：
文献类型：
--
作者：
Nakamura K;Nakabayashi K;Htet Aung K;Aizawa K;Hori N;Yamauchi J;Hata K;Tanoue A
胆管癌（CCA）是一种由胆管细胞肿瘤转化引起的癌症。在肿瘤发生过程中，肿瘤抑制基因和癌症相关基因通常因其启动子区域的异常 DNA 甲基化而沉默。 Zebularine (1-(β-D-呋喃核糖基)-1,2-二氢嘧啶-2-酮) 是 DNA 甲基化的抑制剂，在体外和体内均表现出化学稳定性和最小的细胞毒性。在本研究中，我们探讨了zebularine对CCA细胞的作用和可能的作用机制。我们证明 zebularine 对 CCA 细胞具有抗肿瘤作用。 Zebularine 处理降低了 DNA 甲基转移酶 (DNMT) 蛋白的浓度，并且 DNMT1 敲低导致 CCA 细胞系 TFK-1 和 HuCCT1 中的细胞凋亡。 DNA 甲基化分析表明，zebularine 诱导 DNA 去甲基化，并且发现 GO 生物过程术语“血友病细胞粘附”、“转录调节、DNA 依赖性”和“Wnt 信号通路”显着富集，与去甲基化基因相关。此外，我们观察到 zebularine 处理降低了 TFK-1 和 HuCCT1 细胞中的 β-catenin 蛋白水平。这些结果表明 zebularine 改变 DNA 甲基化状态，并且 zebularine 引起的 DNA 去甲基化的某些方面会诱导 Wnt 信号通路的抑制，从而导致 CCA 中的细胞凋亡。我们之前报道了zebularine通过DNA甲基化独立途径诱导肝细胞癌细胞生长停滞和凋亡的新机制。总之，我们目前和之前的研究表明，zebularine 既可以作为 DNMT 抑制剂，也可以作为非 DNMT 抑制剂试剂，并且虽然 zebularine 的最佳用途可能取决于癌症类型，但 zebularine 可能可用于癌症化疗。
Cholangiocarcinoma (CCA) is a cancer arising from the neoplastic transformation of cholangiocytes. During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions. Zebularine (1-(β-D-ribofuranosyl)-1,2-dihydropyrimidin-2-one) acts as an inhibitor of DNA methylation and exhibits chemical stability and minimal cytotoxicity both in vitro and in vivo. In this study, we explore the effect and possible mechanism of action of zebularine on CCA cells. We demonstrate that zebularine exerts an antitumor effect on CCA cells. Zebularine treatment decreased the concentrations of DNA methyltransferase (DNMT) proteins, and DNMT1 knockdown led to apoptotic cell death in the CCA cell lines TFK-1 and HuCCT1. DNA methylation analysis demonstrated that zebularine induced DNA demethylation, and the GO Biological Process terms “hemophilic cell adhesion”, “regulation of transcription, DNA-dependent” and “Wnt signaling pathway” were found to be significantly enriched in association with demethylated genes. Furthermore, we observed that zebularine treatment decreased β-catenin protein levels in TFK-1 and HuCCT1 cells. These results suggest that zebularine alters DNA methylation status, and that some aspect of DNA demethylation by zebularine induces suppression of the Wnt signaling pathway, which leads to apoptotic cell death in CCA. We previously reported a novel mechanism of zebularine-induced cell growth arrest and apoptosis in hepatocellular carcinoma via a DNA methylation-independent pathway. Together, our present and previous studies indicate that zebularine could function as both a DNMT inhibitor and a non-DNMT inhibitor reagent, and that, while the optimal usage of zebularine may depend on cancer type, zebularine may be useful for chemotherapy against cancer.
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