Identification of methotrexate as a heterochromatin-promoting drug.
Identification of methotrexate as a heterochromatin-promoting drug.
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鉴定甲氨蝶呤作为异染色质促进药物。
DOI：
10.1038/s41598-019-48137-w
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发表时间：
2019
影响因子：
4.6
通讯作者：
Li,WillisX
中科院分区：
文献类型：
--
作者：
Loyola,AndreC;Zhang,Lin;Shang,Robin;Dutta,Pranabananda;Li,Jinghong;Li,WillisX
异染色质是一种紧密堆积的DNA形式，参与基因沉默、染色体分离和保护基因组稳定性。异染色质在肿瘤抑制中的作用越来越被人们所认识，因此可能成为癌症治疗的潜在靶点。然而，到目前为止，还没有药物被很好地建立，以特异性地促进异染色质的形成。在这里，我们描述了一种筛选方法，使用果蝇来鉴定促进异染色质形成的小分子化合物，目的是开发表观遗传癌症疗法。我们利用了一种对异染色质水平敏感的眼睛颜色表型多样化的果蝇品系，并筛选了97种FDA批准的肿瘤药物。在筛选的97种肿瘤药物中，该筛选将甲氨蝶呤确定为促进异染色质形成的最有效的小分子药物。有趣的是，甲氨蝶呤在功能筛选中被鉴定为JAK/STAT抑制剂，导致STAT蛋白磷酸化减少。这些发现与我们先前的观察一致，即未磷酸化的STAT（uSTAT）促进果蝇和人类细胞中异染色质的形成，并抑制小鼠异种移植瘤的生长。因此，具有杂色眼睛颜色表型的果蝇可能是筛选可能作为癌症治疗剂的候选者的异染色质促进化合物的有效工具。
Heterochromatin is a tightly packed form of DNA involved in gene silencing, chromosome segregation, and protection of genome stability. Heterochromatin is becoming more recognized in tumor suppression and may thus serve as a potential target for cancer therapy. However, to date there are no drugs that are well established to specifically promote heterochromatin formation. Here, we describe a screening method usingDrosophilato identify small molecule compounds that promote heterochromatin formation, with the purpose of developing epigenetic cancer therapeutics. We took advantage of aDrosophilastrain with a variegated eye color phenotype that is sensitive to heterochromatin levels, and screened a library of 97 FDA approved oncology drugs. This screen identified methotrexate as the most potent small molecule drug, among the 97 oncology drugs screened, in promoting heterochromatin formation. Interestingly, methotrexate has been identified as a JAK/STAT inhibitor in a functional screen, causing reduced phosphorylation of STAT proteins. These findings are in line with our previous observation that unphosphorylated STAT (uSTAT) promotes heterochromatin formation in bothDrosophilaand human cells and suppresses tumor growth in mouse xenografts. Thus,Drosophilawith variegated eye color phenotypes could be an effective tool for screening heterochromatin-promoting compounds that could be candidates as cancer therapeutics.