KDM3 epigenetically controls tumorigenic potentials of human colorectal cancer stem cells through Wnt/β-catenin signalling.
KDM3 epigenetically controls tumorigenic potentials of human colorectal cancer stem cells through Wnt/β-catenin signalling.
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DOI：
10.1038/ncomms15146
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发表时间：
2017-04-25
影响因子：
16.6
通讯作者：
Wang CY
中科院分区：
文献类型：
--
作者：
Li J;Yu B;Deng P;Cheng Y;Yu Y;Kevork K;Ramadoss S;Ding X;Li X;Wang CY
人类结直肠癌干细胞（CSCs）是一种能够自我更新的肿瘤起始细胞，具有高度的致瘤性和耐药性。虽然与人类结直肠癌发展相关的基因突变是众所周知的，但表观遗传因素如何以及是否特异性地影响人类结直肠癌csc的功能特性却知之甚少。在这里，我们报道KDM3家族的组蛋白去甲基化酶通过表观遗传激活Wnt靶基因转录，在人类结直肠CSCs的致瘤潜能和存活中发挥重要作用。KDM3的缺失抑制人类结直肠癌csc的致瘤生长和化疗耐药。在机制上，KDM3不仅直接擦除抑制H3K9me2标记，还可以帮助募集组蛋白甲基转移酶MLL1促进H3K4甲基化，从而促进Wnt靶基因转录。我们的研究结果表明，KDM3是Wnt信号传导的一个关键表观遗传因子，它协调人类结直肠CSCs的染色质变化和转录，确定了有效消除CSCs的潜在治疗靶点。表观遗传因子可调控人结直肠癌干细胞的功能特性。在这里，作者表明KDM3家族的组蛋白去甲基化酶通过擦除Wnt靶基因上的H3K9me2标记并募集MLL1来促进H3K4甲基化，从而激活结直肠癌干细胞中的Wnt信号。
Human colorectal cancer stem cells (CSCs) are tumour initiating cells that can self-renew and are highly tumorigenic and chemoresistant. While genetic mutations associated with human colorectal cancer development are well-known, little is known about how and whether epigenetic factors specifically contribute to the functional properties of human colorectal CSCs. Here we report that the KDM3 family of histone demethylases plays an important role in tumorigenic potential and survival of human colorectal CSCs by epigenetically activating Wnt target gene transcription. The depletion of KDM3 inhibits tumorigenic growth and chemoresistance of human colorectal CSCs. Mechanistically, KDM3 not only directly erases repressive H3K9me2 marks, but also helps to recruit histone methyltransferase MLL1 to promote H3K4 methylation, thereby promoting Wnt target gene transcription. Our results suggest that KDM3 is a critical epigenetic factor in Wnt signalling that orchestrates chromatin changes and transcription in human colorectal CSCs, identifying potential therapeutic targets for effective elimination of CSCs. Epigenetic factors can regulate functional properties of human colorectal cancer stem cells. Here, the authors show that histone demethylases of the KDM3 family activate Wnt signalling in colorectal cancer stem cells by erasing H3K9me2 marks on Wnt target genes and recruiting MLL1 to promote H3K4 methylation.