NAT COMMUN:表观调节剂Mll1驱动肠道肿瘤发生和干性

2020-12-24 haibei MedSci原创

研究人员发现,组蛋白甲基转移酶Mll1是Wnt驱动的肠癌的调节器。Mll1在Lgr5+干细胞和人结肠癌中高表达,这些细胞的核内β-catenin也有所增加。高水平的MLL1与结肠癌患者的生存率差有关。

Wnt/β-catenin信号可以控制成体干细胞的自我更新,并促进肿瘤发生。已有的研究显示,激活的Wnt/β-catenin信号与结肠癌以及许多其他人类癌症有关。由APC,Gsk3β和Axin1/2组成的破坏复合物的失活可以稳定β-catenin,否则β-catenin会被磷酸化和泛素化的蛋白酶体降解。稳定的β-catenin会转位到细胞核,并结合到Tcf / Lef1转录因子上,诱导靶基因的表达,如Axin2。Wnt信号元件的突变通过促进β-catenin的异常稳定性和超活性来启动肠道肿瘤的发生。

最近,研究人员发现,组蛋白甲基转移酶Mll1是Wnt驱动的肠癌的调节器。Mll1在Lgr5+干细胞和人结肠癌中高表达,这些细胞的核内β-catenin也有所增加。高水平的MLL1与结肠癌患者的生存率差有关。

在Lgr5+肠干细胞中,Mll1基因的敲除可以防止的Wnt/β-catenin驱动的腺瘤形成。Mll1的敲除也可以降低人结肠癌的自我更新,并阻止异种移植的肿瘤生长。

Mll1控制干细胞基因的表达,包括Wnt/β-catenin靶基因Lgr5。Mll1丢失后,干细胞启动子处的组蛋白甲基化从激活性的H3K4三甲基化转换为抑制性的H3K27三甲基化,表明Mll1通过多聚抑制复合物2(PRC2)介导的H3K27三甲基化拮抗基因沉默,从而维持干细胞基因的表达。

对Wnt突变的肠道肿瘤启动细胞的转录组剖析显示,Mll1调控Gata4/6转录因子,已知Gata4/6转录因子可维持癌症细胞干性并控制小叶细胞分化。

因此,该研究结果表明,Mll1是Wnt/β-catenin诱导的肠道肿瘤发生和干性维持的重要表观遗传调节因子。

 

原始出处:

Johanna Grinat et al. The epigenetic regulator Mll1 is required for Wnt-driven intestinal tumorigenesis and cancer stemness. NATURE COMMUNICATIONS (2020). 

 

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    2021-09-14 liuli5079
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    2021-02-08 liye789132251
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    2021-04-16 chenhongpeng
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    2020-12-24 Lizhihua6

    表观调节剂Mll1驱动肠道肿瘤发生和干性

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