Applied Tumor Genomics Research Program, University of Helsinki, Helsinki, Finland.
Research Program in Systems Oncology, University of Helsinki, Helsinki, Finland.
Dev Cell. 2022 Apr 25;57(8):1024-1036.e5. doi: 10.1016/j.devcel.2022.03.018.
The transcription factor Myc drives cell growth across animal phyla and is activated in most forms of human cancer. However, it is unclear which Myc target genes need to be regulated to induce growth and whether multiple targets act additively or if induction of each target is individually necessary. Here, we identified Myc target genes whose regulation is conserved between humans and flies and deleted Myc-binding sites (E-boxes) in the promoters of fourteen of these genes in Drosophila. E-box mutants of essential genes were homozygous viable, indicating that the E-boxes are not required for basal expression. Eight E-box mutations led to Myc-like phenotypes; the strongest mutant, ppan, also made the flies resistant to Myc-induced cell growth without affecting Myc-induced apoptosis. The ppan flies are healthy and display only a minor developmental delay, suggesting that it may be possible to treat or prevent tumorigenesis by targeting individual downstream targets of Myc.
转录因子 Myc 在动物门中驱动细胞生长，并且在大多数人类癌症中被激活。然而，尚不清楚需要调节哪些 Myc 靶基因来诱导生长，以及多个靶标是否是累加作用，还是每个靶标的诱导都是单独必需的。在这里，我们鉴定了 Myc 靶基因，其在人类和果蝇之间的调控是保守的，并在果蝇中删除了这些基因的 14 个启动子中的 Myc 结合位点（E 盒）。必需基因的 E 盒突变体是纯合存活的，这表明 E 盒对于基础表达不是必需的。八个 E 盒突变导致类似于 Myc 的表型；最强的突变体 ppan 也使苍蝇对 Myc 诱导的细胞生长具有抗性，而不影响 Myc 诱导的细胞凋亡。ppan 苍蝇是健康的，只显示轻微的发育延迟，这表明通过针对 Myc 的单个下游靶标，可能有可能治疗或预防肿瘤发生。
