Epigenetic regulation of DACH1, a novel Wnt signaling component in colorectal cancer
Epigenetic regulation of DACH1, a novel Wnt signaling component in colorectal cancer
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DOI：
10.4161/epi.26781
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发表时间：
2013-12-01
期刊：
影响因子：
3.7
通讯作者：
Guo, Mingzhou
中科院分区：
文献类型：
--
作者：
Yan, Wenji;Wu, Kongming;Guo, Mingzhou
结直肠癌（CRC）是世界范围内常见的恶性肿瘤之一。遗传和表观遗传变化都被认为是结直肠癌发生的重要因素。在乳腺癌、前列腺癌和子宫内膜癌中发现了 DACH1 表达缺失。为了分析DACH1在结直肠癌中的调控和功能，本研究采用了5个结直肠癌细胞系、8例正常粘膜、15例息肉和100例原发性结直肠癌。在 CRC 细胞系中，DACH1 表达缺失与启动子区域高甲基化相关，5-Aza-2'-脱氧氮杂胞苷处理可诱导 DACH1 重新表达。我们发现 DACH1 在原发性 CRC 中频繁甲基化，并且这种甲基化与 DACH1 表达的减少相关。这些结果表明，CRC 中 DACH1 表达受到启动子区域高甲基化的调节。 DACH1 甲基化与肿瘤分期晚期、分化差和淋巴结转移相关。 DACH1 的重新表达降低了 TCF/LEF 荧光素酶报告基因活性并抑制 Wnt 信号下游靶标（c-Myc 和 cyclinD1）的表达。在 DACH1 重新表达的 HCT116 细胞异种移植物中，肿瘤尺寸小于对照组。此外，DACH1表达的恢复诱导G2/M期停滞并使HCT116细胞对多西紫杉醇敏感。 DACH1 通过在体外和体内抑制 Wnt 信号传导来抑制 CRC 生长。 DACH1 表达的沉默导致 CRC 细胞对多西紫杉醇产生耐药性。总之，DACH1 在人类 CRC 中频繁甲基化，DACH1 甲基化可作为 CRC 的检测和预后标记。
Colorectal cancer (CRC) is one of the common malignant tumors worldwide. Both genetic and epigenetic changes are regarded as important factors of colorectal carcinogenesis. Loss of DACH1 expression was found in breast, prostate, and endometrial cancer. To analyze the regulation and function of DACH1 in CRC, 5 colorectal cancer cell lines, 8 cases of normal mucosa, 15 cases of polyps and 100 cases of primary CRC were employed in this study. In CRC cell lines, loss of DACH1 expression was correlated with promoter region hypermethylation, and re-expression of DACH1 was induced by 5-Aza-2 '-deoxyazacytidine treatment. We found that DACH1 was frequently methylated in primary CRC and this methylation was associated with reduction in DACH1 expression. These results suggest that DACH1 expression is regulated by promoter region hypermethylation in CRC. DACH1 methylation was associated with late tumor stage, poor differentiation, and lymph node metastasis. Re-expression of DACH1 reduced TCF/LEF luciferase reporter activity and inhibited the expression of Wnt signaling downstream targets (c-Myc and cyclinD1). In xenografts of HCT116 cells in which DACH1 was re-expressed, tumor size was smaller than in controls. In addition, restoration of DACH1 expression induced G2/M phase arrest and sensitized HCT116 cells to docetaxel. DACH1 suppresses CRC growth by inhibiting Wnt signaling both in vitro and in vivo. Silencing of DACH1 expression caused resistance of CRC cells to docetaxel. In conclusion, DACH1 is frequently methylated in human CRC and methylation of DACH1 may serve as detective and prognostic marker in CRC.