文章：

抗坏血酸上调TET活性诱导淋巴瘤细胞的表观遗传调控

Upregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells

原文发布日期：2017-07-21

DOI: 10.1038/bcj.2017.65

类型: Original Article

开放获取: 是

英文摘要：

The Ten Eleven Translocation (TET) enzymes have been found to be mutated in both diffuse large B-cell (DLBCL) and peripheral T-cell (PTCL) lymphomas resulting in DNA hypermethylation. Recent studies in embryonal stem cells showed that ascorbic acid (AA) is a cofactor for TET with a binding site at the catalytic domain, and enhances TET activity. We hypothesized that AA could potentially enhance TET activity in lymphoma cells to cause DNA demethylation, reactivate expression of tumor suppressor genes and enhance chemosensitivity. We demonstrate in vitro that AA treatment of DLBCL and PTCL cells using AA concentrations achievable intravenously increased TET activity leading to DNA demethylation. This epigenetic effect is independent of hydrogen peroxide. AA treatment increased the expression of SMAD1, a tumor suppressor gene known to be suppressed by methylation, and increased chemosensitivity of lymphoma cells. Twenty-nine percent (10/34) of unselected lymphoma patients had plasma AA levels that were deficient suggesting an additional clinical mechanism of TET hypofunction. These data indicate that AA has the potential to modify TET function in lymphoma and enhance chemosensitivity. In addition, the AA deficiency seen in some patients may further impair TET function and contribute to resistance. Clinical trials testing intravenous AA with chemotherapy are warranted.

摘要翻译： 

十一易位（TET）酶被发现在弥漫大B细胞（DLBCL）和外周T细胞（PTCL）淋巴瘤中均发生突变，导致DNA高甲基化。最近在胚胎干细胞中的研究表明，抗坏血酸（AA）是TET的辅因子，其结合位点位于催化结构域，并能增强TET活性。我们假设AA可能潜在地增强淋巴瘤细胞中TET的活性，引起DNA去甲基化，重新激活抑癌基因的表达并增强化疗敏感性。我们在体外实验中证明，使用静脉注射可达浓度的AA处理DLBCL和PTCL细胞，能增加TET活性，从而导致DNA去甲基化。这种表观遗传效应与过氧化氢无关。AA处理增加了SMAD1（一种已知因甲基化而受抑制的抑癌基因）的表达，并提高了淋巴瘤细胞的化疗敏感性。在未加选择的淋巴瘤患者中，29%（10/34）的患者血浆AA水平不足，这提示了TET功能减弱的另一种临床机制。这些数据表明，AA具有改变淋巴瘤中TET功能并增强化疗敏感性的潜力。此外，部分患者存在的AA缺乏可能进一步损害TET功能并导致耐药性。有必要开展静脉注射AA联合化疗的临床试验。

原文链接：

Upregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells