5-Carboxylcytosine levels are elevated in human breast cancers and gliomas.
5-Carboxylcytosine levels are elevated in human breast cancers and gliomas.
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DOI：
10.1186/s13148-015-0117-x
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发表时间：
2015
影响因子：
5.7
通讯作者：
Ruzov A
中科院分区：
文献类型：
--
作者：
Eleftheriou M;Pascual AJ;Wheldon LM;Perry C;Abakir A;Arora A;Johnson AD;Auer DT;Ellis IO;Madhusudan S;Ruzov A
DNA甲基化（5-甲基胞嘧啶（5mC））模式在癌症中经常发生改变。10 - 11易位（Tet）蛋白将5mC氧化为5-羟甲基胞嘧啶（5hmC）、5-甲酰基胞嘧啶（5fC）和5-羧基胞嘧啶（5caC）。除了它们假定的特定生物学作用外，这些氧化形式的5mC可能在去甲基化过程中充当中间体。根据几份报告，癌症患者的5hmC水平显著降低；然而，5fC和5caC在恶性组织中的分布尚未研究。在这里，我们用免疫化学方法检测了28例正常乳腺组织样本、59例侵袭性乳腺癌样本和74例胶质瘤样本中的5hmC和5caC水平。与之前的报道一致，我们发现71%的正常乳腺样本显示出强烈的5hmC信号，而只有18%的乳腺癌样本具有相同水平的5hmC染色。出乎意料的是，尽管在正常乳腺组织中检测不到5caC，但27%的乳腺癌样本显示出这种修饰的显著染色（p < 0.001）。令人惊讶的是，在乳腺癌组织中，免疫化学检测到的5caC的存在与5hmC信号的强度无关。在胶质瘤中，我们发现在45%的肿瘤中可以检测到5caC。我们证明，与5hmC不同，在乳腺癌和胶质瘤中，5caC水平升高。我们的研究结果揭示了癌症表观基因组的另一种复杂性，表明活性去甲基化和/或5ac依赖性转录调控在一些肿瘤中被预激活，并可能有助于其发病机制。有必要进行更大规模的研究来评估5caC在癌症中的临床病理意义。
DNA methylation (5-methylcytosine (5mC)) patterns are often altered in cancers. Ten-eleven translocation (Tet) proteins oxidise 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). In addition to their presumptive specific biological roles, these oxidised forms of 5mC may serve as intermediates in demethylation process. According to several reports, 5hmC levels are strongly decreased in cancers; however, the distribution of 5fC and 5caC in malignant tissue has not been studied. Here, we examine the levels of 5hmC and 5caC in 28 samples of normal breast tissue, 59 samples of invasive human breast cancer and 74 samples of gliomas using immunochemistry. In agreement with previous reports, we show that 71 % of normal breast samples exhibit strong 5hmC signal, compared with only 18 % of breast cancer samples with equivalent levels of 5hmC staining. Unexpectedly, although 5caC is not detectable in normal breast tissue, 27 % of breast cancer samples exhibit significant staining for this modification (p < 0.001). Surprisingly, the presence of immunochemically detectable 5caC is not associated with the intensity of 5hmC signal in breast cancer tissue. In gliomas, we show that 5caC is detectable in 45 % of tumours. We demonstrate that, unlike 5hmC, the levels of 5caC are elevated in a proportion of breast cancers and gliomas. Our results reveal another level of complexity to the cancer epigenome, suggesting that active demethylation and/or 5caC-dependent transcriptional regulation are pre-activated in some tumours and may contribute to their pathogenesis. Larger studies to evaluate the clinicopathological significance of 5caC in cancers are warranted.