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首页> 外文期刊>Epigenetics: official journal of the DNA Methylation Society >The TCF4/β-catenin pathway and chromatin structure cooperate to regulate D-glucuronyl C5-epimerase expression in breast cancer
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The TCF4/β-catenin pathway and chromatin structure cooperate to regulate D-glucuronyl C5-epimerase expression in breast cancer

机译：TCF4 /β-catenin途径与染色质结构协同调节乳腺癌中D-葡萄糖醛酸C5-表异构酶的表达

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摘要

D-glucuronyl C5-epimerase (GLCE) is a potential tumor-suppressor gene involved in heparan sulfate biosynthesis. GLCE expression is significantly decreased in breast tumors; however, the underlying molecular mechanisms remain unclear. This study examined the possible epigenetic mechanisms for GLCE inactivation in breast cancer. Very little methylation of the GLCE promoter region was detected in breast tumors in vivo and in breast cancer cells (MCF7 and T47D) in vitro and GLCE expression in breast cancer cells was not altered by 5-deoxyazacytidine (5-aza-dC) treatment, suggesting that promoter methylation is not involved in regulating GLCE expression. Chromatin activation by Trichostatin A (TSA) or 5-aza-dC/TSA treatment increased GLCE expression by two to 3-fold due to an increased interaction between the GLCE promoter and the TCF4/β-catenin transactivation complex, or H3K9ac and H3K4Me3 histone modifications. However, ectopic expression of TCF4/β-catenin was not sufficient to activate GLCE expression in MCF7 cells, suggesting that chromatin structure plays a key role in GLCE regulation. Although TSA treatment significantly repressed canonical WNT signaling in MCF7 cells, it did not influence endogenous TCF4/β-catenin mRNA levels and activated TCF4/β-catenin-driven transcription from the GLCE promoter, indicating GLCE as a novel target for TCF4/β-catenin complex in breast cancer cells. A correlation was observed between GLCE, TCF4 and β-catenin expression in breast cancer cells and primary tumors, suggesting an important role for TCF4/β-catenin in regulating GLCE expression both in vitro and in vivo. Taken together, the results indicate that GLCE expression in breast cancer is regulated by a combination of chromatin structure and TCF4/β-catenin complex activity.
机译：D-葡糖醛酸酰基C5-表异构酶（GLCE）是涉及硫酸乙酰肝素生物合成的潜在肿瘤抑制基因。 GLCE表达在乳腺肿瘤中明显降低;然而，潜在的分子机制仍不清楚。这项研究检查了乳腺癌中GLCE失活的可能的表观遗传机制。在体内和体外乳腺癌细胞（MCF7和T47D）中检测到极少量的GLCE启动子区域甲基化，并且5-脱氧氮胞苷（5-aza-dC）处理未改变乳腺癌细胞中GLCE的表达，提示启动子甲基化不参与调节GLCE表达。 Trichostatin A（TSA）或5-aza-dC / TSA处理对染色质的激活使GLCE表达增加了2到3倍，这是因为GLCE启动子与TCF4 /β-catenin反式激活复合物或H3K9ac和H3K4Me3组蛋白之间的相互作用增加了修改。然而，TCF4 /β-catenin的异位表达不足以激活MCF7细胞中GLCE的表达，这表明染色质结构在GLCE调控中起关键作用。尽管TSA处理可显着抑制MCF7细胞中的经典WNT信号传导，但它不会影响内源性TCF4 /β-cateninmRNA水平和GLCE启动子激活的TCF4 /β-catenin驱动的转录，表明GLCE是TCF4 /β-的新靶标乳腺癌细胞中的连环蛋白复合物。在乳腺癌细胞和原发性肿瘤中观察到GLCE，TCF4和β-catenin表达之间的相关性，表明TCF4 /β-catenin在体内和体外调节GLCE表达中具有重要作用。两者合计，结果表明乳腺癌中的GLCE表达受染色质结构和TCF4 /β-catenin复合物活性的组合调节。

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