Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD.
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD.
Int J Cancer. 2019 Dec 15;145(12):3425-3435. doi: 10.1002/ijc.32587. Epub 2019 Aug 9.
DNA methylation has long been recognized as a tumor-promoting factor when aberrantly regulated in the promoter region of genes. However, the effect of intragenic DNA methylation remains poorly understood on the clinical aspects of cancer. Here, we first evaluated the significance of intragenic DNA methylation for survival outcomes of cancer patients in a genome-wide manner. Glioblastoma patients with hypermethylated intragenic regions exhibited better survival than hypomethylated patients. Enrichment analyses of intragenic DNA methylation profiles with epigenetic signatures prioritized the intragenic DNA methylation of ZMIZ1 as a possible glioblastoma prognostic marker that is independent of MGMT methylation in IDH1 wild-type patients. This intragenic region harbored molecular signatures of alternative transcription across many cell types. Furthermore, we found that the intragenic region of ZMIZ1 can serve as a molecular marker in multiple cancers including astrocytomas, bladder cancer and renal cell carcinoma according to DNA methylation status. Finally, in vitro and in vivo experiments uncovered the role of ZMIZ1 as a driver of tumor cell migration. Altogether, our results identify ZMIZ1 as a prognostic marker in cancer and highlight the clinical significance of intragenic methylation in cancer.
DNA 甲基化在基因启动子区域异常调节时，长期以来一直被认为是促进肿瘤的因素。然而，基因内 DNA 甲基化对癌症临床方面的影响仍知之甚少。在这里，我们首次以全基因组的方式评估了基因内 DNA 甲基化对癌症患者生存结果的意义。具有高甲基化基因内区域的胶质母细胞瘤患者比低甲基化患者的生存情况更好。通过对基因内 DNA 甲基化谱与表观遗传特征的富集分析，将 ZMIZ1 的基因内 DNA 甲基化作为一种可能的胶质母细胞瘤预后标志物进行了优先排序，该标志物在 IDH1 野生型患者中独立于 MGMT 甲基化。该基因内区域在许多细胞类型中具有替代转录的分子特征。此外，根据 DNA 甲基化状态，我们发现 ZMIZ1 的基因内区域可以作为包括星形细胞瘤、膀胱癌和肾细胞癌在内的多种癌症的分子标志物。最后，体外和体内实验揭示了 ZMIZ1 作为肿瘤细胞迁移驱动因子的作用。总之，我们的研究结果确定 ZMIZ1 是癌症的预后标志物，并强调了基因内甲基化在癌症中的临床意义。
