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表观遗传调控因子 Mll1 对于 Wnt 驱动的肠道肿瘤发生和癌症干性是必需的。

The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness.

机构信息

Cancer Research Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, 13125, Berlin, Germany.

Division of Gastroenterology and Hepatology, Medical Department, Charité University Medicine, 13353, Berlin, Germany.

出版信息

Nat Commun. 2020 Dec 21;11(1):6422. doi: 10.1038/s41467-020-20222-z.

DOI:10.1038/s41467-020-20222-z
PMID:33349639
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7752919/
Abstract

Wnt/β-catenin signaling is crucial for intestinal carcinogenesis and the maintenance of intestinal cancer stem cells. Here we identify the histone methyltransferase Mll1 as a regulator of Wnt-driven intestinal cancer. Mll1 is highly expressed in Lgr5 stem cells and human colon carcinomas with increased nuclear β-catenin. High levels of MLL1 are associated with poor survival of colon cancer patients. The genetic ablation of Mll1 in mice prevents Wnt/β-catenin-driven adenoma formation from Lgr5 intestinal stem cells. Ablation of Mll1 decreases the self-renewal of human colon cancer spheres and halts tumor growth of xenografts. Mll1 controls the expression of stem cell genes including the Wnt/β-catenin target gene Lgr5. Upon the loss of Mll1, histone methylation at the stem cell promoters switches from activating H3K4 tri-methylation to repressive H3K27 tri-methylation, indicating that Mll1 sustains stem cell gene expression by antagonizing gene silencing through polycomb repressive complex 2 (PRC2)-mediated H3K27 tri-methylation. Transcriptome profiling of Wnt-mutated intestinal tumor-initiating cells reveals that Mll1 regulates Gata4/6 transcription factors, known to sustain cancer stemness and to control goblet cell differentiation. Our results demonstrate that Mll1 is an essential epigenetic regulator of Wnt/β-catenin-induced intestinal tumorigenesis and cancer stemness.

摘要

Wnt/β-catenin 信号通路对于肠道肿瘤的发生和维持肠道肿瘤干细胞至关重要。在此，我们发现组蛋白甲基转移酶 Mll1 是 Wnt 驱动肠道肿瘤的调节因子。Mll1 在 Lgr5 干细胞和核β-catenin 水平升高的人类结肠癌中高度表达。高水平的 MLL1 与结肠癌患者的预后不良相关。在小鼠中敲除 Mll1 可防止 Wnt/β-catenin 驱动的 Lgr5 肠干细胞腺瘤的形成。Mll1 的缺失减少了人结肠癌球体的自我更新，并阻止了异种移植肿瘤的生长。Mll1 控制着包括 Wnt/β-catenin 靶基因 Lgr5 在内的干细胞基因的表达。当 Mll1 缺失时，干细胞启动子上的组蛋白甲基化从激活 H3K4 三甲基化转变为抑制 H3K27 三甲基化，表明 Mll1 通过抑制沉默复合物 2（PRC2）介导的 H3K27 三甲基化来拮抗基因沉默，从而维持干细胞基因表达。Wnt 突变的肠道肿瘤起始细胞的转录组分析表明，Mll1 调节 Gata4/6 转录因子，已知其维持癌症干细胞特性并控制杯状细胞分化。我们的研究结果表明，Mll1 是 Wnt/β-catenin 诱导的肠道肿瘤发生和癌症干细胞特性的必需表观遗传调节剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d5d/7752919/651c539180f7/41467_2020_20222_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d5d/7752919/3228bf341f7a/41467_2020_20222_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d5d/7752919/e8bbc862d2bb/41467_2020_20222_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d5d/7752919/988fb69a2dd9/41467_2020_20222_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d5d/7752919/1fc513063249/41467_2020_20222_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d5d/7752919/b141f4ea2b40/41467_2020_20222_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d5d/7752919/651c539180f7/41467_2020_20222_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d5d/7752919/3228bf341f7a/41467_2020_20222_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d5d/7752919/e8bbc862d2bb/41467_2020_20222_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d5d/7752919/988fb69a2dd9/41467_2020_20222_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d5d/7752919/1fc513063249/41467_2020_20222_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d5d/7752919/b141f4ea2b40/41467_2020_20222_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d5d/7752919/651c539180f7/41467_2020_20222_Fig6_HTML.jpg

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