Epigenetic activation of Wnt/β-catenin signaling plays a critical role in Wnt-induced tumorigenesis, notably in colorectal cancers. KDM3 and KDM4 histone demethylases have been reported to promote oncogenic Wnt signaling through demethylation of H3K9 on Wnt target gene promoters and are suggested to be potential therapeutic targets. However, potent inhibitors for these regulators are still not available. In addition, which family is most responsible for activation of Wnt target genes and Wnt-induced oncogenesis is not well documented, specifically in colorectal cancer. In this study, we characterized the functional redundancy and differences between KDM3 and KDM4 in regard to regulating Wnt signaling. Our data suggest that KDM3 may play a more essential role than KDM4 in regulating oncogenic Wnt signaling in human colorectal cancer. We also identified that IOX1, a known histone demethylase inhibitor, significantly suppresses Wnt target gene transcription and colorectal cancer tumorigenesis. Mechanistically, IOX1 inhibits the enzymatic activity of KDM3 by binding to the Jumonji C domain and thereby preventing the demethylation of H3K9 on Wnt target gene promoters. Taken together, our data not only identified the critical mechanisms by which IOX1 suppressed Wnt/β-catenin signaling and colorectal cancer tumorigenesis through inhibition of KDM3, but also suggested that IOX1 may represent an attractive small molecule lead for future drug design and discovery.

中文翻译：

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IOX1 通过抑制 KDM3 组蛋白去甲基酶来抑制 Wnt 靶基因转录和结直肠癌肿瘤发生


Wnt/β-连环蛋白信号的表观遗传激活在 Wnt 诱导的肿瘤发生中发挥着关键作用，特别是在结直肠癌中。据报道，KDM3 和 KDM4 组蛋白去甲基化酶可通过 Wnt 靶基因启动子上的 H3K9 去甲基化来促进致癌 Wnt 信号传导，并被认为是潜在的治疗靶点。然而，仍然没有这些调节剂的有效抑制剂。此外，哪个家族对 Wnt 靶基因的激活和 Wnt 诱导的肿瘤发生负有最大责任，目前还没有很好的记录，特别是在结直肠癌中。在本研究中，我们描述了 KDM3 和 KDM4 在调节 Wnt 信号传导方面的功能冗余和差异。我们的数据表明，KDM3 在调节人类结直肠癌致癌 Wnt 信号传导方面可能比 KDM4 发挥更重要的作用。我们还发现，IOX1（一种已知的组蛋白去甲基酶抑制剂）可显着抑制 Wnt 靶基因转录和结直肠癌肿瘤发生。从机制上讲，IOX1 通过与 Jumonji C 结构域结合来抑制 KDM3 的酶活性，从而防止 Wnt 靶基因启动子上 H3K9 的去甲基化。总而言之，我们的数据不仅确定了 IOX1 通过抑制 KDM3 抑制 Wnt/β-catenin 信号传导和结直肠癌肿瘤发生的关键机制，而且还表明 IOX1 可能代表未来药物设计和发现的有吸引力的小分子先导。