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首页> 外文期刊>EMBO Journal >Wnt/β-catenin signalling induces MLL to create epigenetic changes in salivary gland tumours
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Wnt/β-catenin signalling induces MLL to create epigenetic changes in salivary gland tumours

机译：Wnt /β连环蛋白信号诱导MLL创建唾腺肿瘤表观遗传变化

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摘要

We show that activation of Wnt/β-catenin and attenuation of Bmp signals, by combined gain- and loss-of-function mutations of β-catenin and Bmpr1a, respectively, results in rapidly growing, aggressive squamous cell carcinomas (SCC) in the salivary glands of mice. Tumours contain transplantable and hyperproliferative tumour propagating cells, which can be enriched by fluorescence activated cell sorting (FACS). Single mutations stimulate stem cells, but tumours are not formed. We show that β-catenin, CBP and Mll promote self-renewal and H3K4 tri-methylation in tumour propagating cells. Blocking β-catenin-CBP interaction with the small molecule ICG-001 and small-interfering RNAs against β-catenin, CBP or Mll abrogate hyperproliferation and H3K4 tri-methylation, and induce differentiation of cultured tumour propagating cells into acini-like structures. ICG-001 decreases H3K4me3 at promoters of stem cell-associated genes in vitro and reduces tumour growth in vivo. Remarkably, high Wnt/β-catenin and low Bmp signalling also characterize human salivary gland SCC and head and neck SCC in general. Our work defines mechanisms by which β-catenin signals remodel chromatin and control induction and maintenance of tumour propagating cells. Further, it supports new strategies for the therapy of solid tumours.
机译：我们表明,激活的Wnt /β连环蛋白和Bmp信号的衰减,增益和相结合丧失突变的β连环蛋白和分别Bmpr1a导致快速增长,积极的鳞状细胞癌(SCC)唾液腺的老鼠。可移植和hyperproliferative肿瘤繁殖的细胞,可丰富了荧光激活细胞分类(流式细胞仪)。单突变刺激干细胞,但是肿瘤形成。海关与边境保护局和Mll促进自我更新和H3K4tri-methylation在肿瘤细胞繁殖。阻断β-catenin-CBP交互与小的协调小组- 001和携带rna分子对β连环蛋白,CBP或Mll废除hyperproliferation and H3K4 tri-methylation, and诱导分化培养的肿瘤传播细胞acini-like结构。协调小组- 001减少H3K4me3茎的推动者体外,减少肿瘤细胞相关基因增长的体内。和低Bmp信号也描述人类唾腺鳞状细胞癌、头颈部鳞状细胞癌将军。β连环蛋白信号改变染色质和控制诱导和维持肿瘤传播细胞。固体肿瘤的治疗。

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