BACKGROUND Cancer still is one of the leading causes of death and its death toll is predicted to rise further. We identified earlier the potential tumour suppressor zygote arrest 1 (ZAR1) to play a role in lung carcinogenesis through its epigenetic inactivation. RESULTS We are the first to report that ZAR1 is epigenetically inactivated not only in lung cancer but also across cancer types, and ZAR1 methylation occurs across its complete CpG island. ZAR1 hypermethylation significantly correlates with its expression reduction in cancers. We are also the first to report that ZAR1 methylation and expression reduction are of clinical importance as a prognostic marker for lung cancer and kidney cancer. We further established that the carboxy (C)-terminally present zinc-finger of ZAR1 is relevant for its tumour suppression function and its protein partner binding associated with the mRNA/ribosomal network. Global gene expression profiling supported ZAR1's role in cell cycle arrest and p53 signalling pathway, and we could show that ZAR1 growth suppression was in part p53 dependent. Using the CRISPR-dCas9 tools, we were able to prove that epigenetic editing and reactivation of ZAR1 is possible in cancer cell lines. CONCLUSION ZAR1 is a novel cancer biomarker for lung and kidney, which is epigenetically silenced in various cancers by DNA hypermethylation. ZAR1 exerts its tumour suppressive function in part through p53 and through its zinc-finger domain. Epigenetic therapy can reactivate the ZAR1 tumour suppressor in cancer.

中文翻译：

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新型肿瘤抑制因子ZAR1的表观遗传治疗及其癌症生物标志物功能。

背景技术癌症仍然是主要的死亡原因之一，其死亡人数预计将进一步上升。我们更早地确定了潜在的肿瘤抑制合子逮捕1（ZAR1）通过其表观遗传失活在肺癌发生中发挥作用。结果我们是第一个报道ZAR1不仅在肺癌中而且在所有癌症类型中均在表观遗传学上失活，并且ZAR1甲基化发生在其整个CpG岛上。ZAR1高度甲基化与其在癌症中的表达降低显着相关。我们也是第一个报道ZAR1甲基化和表达降低作为肺癌和肾癌的预后标志物具有临床重要性的人。我们进一步确定，ZAR1的羧基（C）末端存在的锌指与其抑癌功能及其与mRNA /核糖体网络相关的蛋白伴侣结合有关。全局基因表达谱支持ZAR1在细胞周期停滞和p53信号通路中的作用，我们可以证明ZAR1的生长抑制部分依赖于p53。使用CRISPR-dCas9工具，我们能够证明ZAR1的表观遗传编辑和再激活在癌细胞系中是可能的。结论ZAR1是一种新型的肺癌和肾脏癌生物标志物，通过DNA高甲基化在各种癌症中被表观遗传沉默。ZAR1部分通过p53和锌指结构域发挥其抑癌功能。表观遗传学治疗可以重新激活癌症中的ZAR1肿瘤抑制因子。