Department of Pathology, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China.
Oncogene. 2019 May;38(18):3488-3503. doi: 10.1038/s41388-018-0671-8. Epub 2019 Jan 16.
Recently, nuclear poly-ADP-ribosylation had aroused research interest in epigenetics, but little attempt to explore functions of mono-ADP-ribosylation of histone, the major formation of histone ADP-ribosylated modification. We have previously reported a novel mono-ADP-ribosylation of H3R117, which promoted proliferation of LoVo cells. Here we showed that mono-ADP-ribosylated H3R117 of LoVo cells depressed demethylation of tumor suppressor TFPI2 promoter by suppressing TET1 expression and adjusting H3K9me3 enrichment of TFPI2 promoter to attenuate affinity of TET1, besides, since high H3K27me3 level was associated with hypermethylation, mono-ADP-ribosylated-H3R117-depended-H3K27me3 of TFPI2 promoter may contribute to hypermethylation of TFPI2. However, H3R117A mutation increased poly-ADP-ribosylated modification of TET1 promoter not TFPI2 promoter, which resulted in boosting transcription and expression of TET1 by altering DNA methylated modification, chromatin accessibility, and histone-methylated modification of TET1 promoter, while knockout TET1 of H3R117A LoVo cells directly led to hypermethylation of TFPI2 promoter and depression of TFPI2 secretion as well as enhanced proliferation, suggested that TET1 played a key role in demethylation of TFPI2, production of TFPI2, and cell proliferation. Bioinformatics analyses reveal prevalent hypermethylation of TFPI2 was an early event in tumorigenesis of colorectal caner, and expression of TET1 and TFPI2 was positive correlation in colorectal cancer and normal tissue. These data suggested that mono-ADP-ribosylation of H3R117 upregulated methylation of TFPI2 by impact TET1, since hypermethyaltion of TFPI2 was an early event in tumorigenesis, selectively target mono-ADP-ribosylation of H3R117 deficiency could be a feasible way to block tumorigenesis of colorectal cancer.
最近，核多聚 ADP-核糖基化在表观遗传学中引起了研究兴趣，但对组蛋白单 ADP-核糖基化的功能研究甚少，组蛋白 ADP-核糖基化修饰的主要形式。我们之前报道了一种新型的 H3R117 单 ADP-核糖基化，它促进了 LoVo 细胞的增殖。在这里，我们发现 LoVo 细胞中单 ADP-核糖基化的 H3R117 通过抑制 TET1 表达和调节 TFPI2 启动子上的 H3K9me3 富集来抑制 TET1 的亲和力，从而抑制 TFPI2 启动子的去甲基化，此外，由于高 H3K27me3 水平与高甲基化相关，TFPI2 启动子上的单 ADP-核糖基化-H3R117 依赖性 H3K27me3 可能有助于 TFPI2 的高甲基化。然而，H3R117A 突变增加了 TET1 启动子而不是 TFPI2 启动子的多 ADP-核糖基化修饰，这导致通过改变 TET1 启动子的 DNA 甲基化修饰、染色质可及性和组蛋白甲基化修饰来促进 TET1 的转录和表达，而 H3R117A LoVo 细胞中 TET1 的敲除则直接导致 TFPI2 启动子的高甲基化和 TFPI2 的分泌减少以及细胞增殖增强，表明 TET1 在 TFPI2 的去甲基化、TFPI2 的产生和细胞增殖中发挥关键作用。生物信息学分析表明，TFPI2 的高甲基化是结直肠癌发生的早期事件，并且 TET1 和 TFPI2 在结直肠癌和正常组织中的表达呈正相关。这些数据表明，H3R117 的单 ADP-核糖基化通过影响 TET1 而上调 TFPI2 的甲基化，由于 TFPI2 的高甲基化是肿瘤发生的早期事件，因此选择性靶向 H3R117 单 ADP-核糖基化的缺乏可能是阻止结直肠癌发生的可行方法。
