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首页> 外文期刊>Epigenetics: official journal of the DNA Methylation Society >Epigenetic regulation of DACH1, a novel Wnt signaling component in colorectal cancer
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Epigenetic regulation of DACH1, a novel Wnt signaling component in colorectal cancer

机译：DACH1的表观遗传调控，结直肠癌中的新型Wnt信号成分

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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.
机译：大肠癌（CRC）是全世界常见的恶性肿瘤之一。遗传和表观遗传变化均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DACH1表达缺失。为了分析DACH1在CRC中的调控和功能，本研究采用了5种结直肠癌细胞系，8例正常黏膜，15例息肉和100例原发性CRC。在CRC细胞系中，DACH1表达的缺失与启动子区域甲基化相关，并且通过5-Aza-2'-脱氧氮胞苷处理诱导DACH1的重新表达。我们发现DACH1在原发性CRC中经常被甲基化，而这种甲基化与DACH1表达的降低有关。这些结果表明，DACH1的表达受CRC中启动子区域甲基化的调节。 DACH1甲基化与肿瘤晚期，分化差和淋巴结转移有关。 DACH1的重新表达降低了TCF / LEF荧光素酶报道分子的活性，并抑制了Wnt信号传导下游靶标（c-Myc和cyclinD1）的表达。在DACH1重新表达的HCT116细胞的异种移植物中，肿瘤的大小小于对照组。此外，DACH1表达的恢复诱导G2 / M期阻滞并使HCT116细胞对多西他赛敏感。 DACH1通过在体内外抑制Wnt信号传导来抑制CRC的生长。 DACH1表达的沉默导致CRC细胞对多西他赛的抗性。总之，DACH1在人CRC中经常被甲基化，而DACH1的甲基化可能在CRC中起检测和预后的作用。

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