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Moderate DNA hypomethylation suppresses intestinal tumorigenesis by promoting caspase-3 expression and apoptosis
Oncogenesis ( IF 6.2 ) Pub Date : 2021-05-04 , DOI: 10.1038/s41389-021-00328-9
Xiaoya Duan , Yuanyong Huang , Xiaoxing Chen , Wencai Wang , Jiwei Chen , Jialun Li , Wei Yang , Jiwen Li , Qihan Wu , Jiemin Wong

Global DNA hypomethylation is a most common epigenetic alteration in human neoplasia. However, accumulative evidence shows that global DNA hypomethylation impacts tumorigenesis in a tissue-specific manner, promoting tumorigenesis in some but suppressing tumorigenesis in others including colorectal cancer. The underlying mechanisms, especially how DNA hypomethylation suppresses tumorigenesis, remain largely unknown. Here, we investigate how DNA hypomethylation affects intestinal tumorigenesis by using an Uhrf1 tandem tudor domain knockin mutant mouse model (Uhrf1ki/ki) that exhibits a moderate ~10% reduction of global DNA methylation. We found that both chemical-induced colorectal carcinogenesis and Apc loss of heterozygosity (LOH)-induced intestinal tumorigenesis are substantially suppressed in the Uhrf1 mutant mice. Furthermore, unlike Dnmt1 hypomorphic mice in which DNA hypomethylation suppresses the incidence of macroscopic intestinal tumors but promotes the formation of microadenoma in ApcMin/+ background, Uhrf1ki/ki/ApcMin/+ mice have markedly reduced incidence of both microadenoma and macroadenoma. DNA hypomethylation does not appear to affect Apc LOH, activation of the Wnt or Hippo pathway, or tumor cell proliferation, but acts cooperatively with activated Wnt pathway to enhance the caspase-3 gene expression, activation, and apoptosis. Furthermore, increased caspase-3 expression correlates with DNA hypomethylation within the caspase-3 enhancer regions. Taken together, we present a new mouse model for investigating the role of and the molecular mechanisms by which DNA hypomethylation suppresses intestinal tumorigenesis. Our finding that a moderate DNA hypomethylation is sufficient to suppress intestinal tumorigenesis by promoting caspase-3 expression and apoptosis sheds new light on DNA-methylation inhibitor-based colorectal cancer therapeutics.



中文翻译:

适度的DNA低甲基化通过促进caspase-3表达和凋亡来抑制肠道肿瘤发生

全局DNA低甲基化是人类肿瘤中最常见的表观遗传学改变。但是,累积的证据表明,整体DNA甲基化不足以组织特异性方式影响肿瘤发生,在某些情况下促进肿瘤发生,而在其他方面(包括结直肠癌)则抑制肿瘤发生。潜在的机制,特别是DNA低甲基化如何抑制肿瘤发生的机制,仍是未知之数。在这里,我们调查DNA低甲基化如何通过使用Uhrf1串联的tudor域敲入突变小鼠模型(Uhrf1 ki / ki)来影响肠道肿瘤发生,该模型表现出总体DNA甲基化程度降低约10%。我们发现化学诱导的大肠癌发生和ApcUhrf1突变小鼠中,杂合性(LOH)诱导的肠道肿瘤发生的丧失得到了显着抑制。此外,不同于Dnmt1亚型小鼠,其中DNA低甲基化抑制了宏观肠道肿瘤的发生,但促进了Apc Min / +背景下微腺瘤的形成,Uhrf1 ki / ki / Apc Min / +小鼠显着降低了微腺瘤和大腺瘤的发生率。DNA低甲基化似乎不影响ApcLOH,Wnt或Hippo途径的激活或肿瘤细胞增殖,但与激活的Wnt途径协同作用,以增强caspase-3基因的表达,激活和凋亡。此外,增加的caspase-3表达与caspase-3增强子区域内的DNA低甲基化有关。综上所述,我们提出了一种新的小鼠模型,用于研究DNA低甲基化抑制肠道肿瘤发生的作用及其分子机制。我们的发现,适度的DNA低甲基化足以通过促进caspase-3表达来抑制肠道肿瘤发生,而凋亡则为基于DNA甲基化抑制剂的结直肠癌治疗方法提供了新的思路。

更新日期:2021-05-05
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