Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Biochem Pharmacol. 2013 Apr 15;85(8):1042-56. doi: 10.1016/j.bcp.2013.01.012. Epub 2013 Jan 24.
Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, AdOx disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity.
转甲基作用是一种重要的反应，它将 S-腺苷甲硫氨酸（SAM）中的甲基转移到 DNA、RNA 和蛋白质等底物上。已知转甲基作用在各种细胞反应中起着关键作用。在这项研究中，我们使用腺苷同型半胱氨酸（SAH）上调策略作为负反馈抑制剂，研究了转甲基作用对肿瘤发生反应的影响及其调节机制。腺苷二醛（AdOx）是一种抑制转甲基抑制性腺苷同型半胱氨酸（SAH）水解酶（SAHH）的抑制剂，它能提高 SAH 的水平，有效地阻止癌细胞的增殖、迁移和侵袭；还能诱导 C6 神经胶质瘤细胞分化，并以剂量依赖的方式抑制鸡蛋的新生血管生成。通过免疫印迹分析，发现 AdOx 能够间接降低致癌性 Src 的磷酸化及其激酶活性。有趣的是，AdOx 破坏了肌动蛋白细胞骨架结构，导致形态发生变化，并抑制了由 Src 和 p85/PI3K 组成的信号复合物的形成，该复合物与各种肿瘤发生反应有关。与这些数据一致的是，外源性 SAH 处理或通过特异性 siRNA 或另一种抑制剂 3-脱氮腺苷（DAZA）抑制 SAHH，同样会产生抗肿瘤反应，抑制 Src 的活性，改变肌动蛋白细胞骨架，并改变肌动蛋白和 Src 之间的共定位模式。总之，这些结果表明，SAH/SAHH 介导的转甲基作用可能通过肌动蛋白细胞骨架和 Src 激酶活性之间的交叉调节与肿瘤发生过程有关。
