Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
Sci Rep. 2019 Aug 12;9(1):11673. doi: 10.1038/s41598-019-48137-w.
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 using Drosophila to identify small molecule compounds that promote heterochromatin formation, with the purpose of developing epigenetic cancer therapeutics. We took advantage of a Drosophila strain 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 both Drosophila and human cells and suppresses tumor growth in mouse xenografts. Thus, Drosophila with variegated eye color phenotypes could be an effective tool for screening heterochromatin-promoting compounds that could be candidates as cancer therapeutics.
异染色质是一种紧密包装的 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越来越受到重视，因此可能成为癌症治疗的潜在靶点。然而，迄今为止，没有哪种药物被很好地确立为专门促进异染色质形成。在这里，我们描述了一种使用果蝇筛选可促进异染色质形成的小分子化合物的筛选方法，目的是开发表观遗传癌症治疗药物。我们利用一种果蝇品系，其眼睛颜色表现为斑驳，对异染色质水平敏感，筛选了 97 种 FDA 批准的肿瘤药物文库。该筛选发现，在 97 种筛选的肿瘤药物中，甲氨蝶呤是促进异染色质形成的最有效小分子药物之一。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 蛋白的磷酸化减少。这些发现与我们之前的观察结果一致，即未磷酸化的 STAT(uSTAT)在果蝇和人类细胞中促进异染色质形成，并抑制小鼠异种移植中的肿瘤生长。因此，具有斑驳眼睛颜色表型的果蝇可能是筛选促进异染色质形成的化合物的有效工具，这些化合物可能成为癌症治疗的候选药物。
