ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice.
ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice.
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DOI：
10.1038/ng.3744
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发表时间：
2017-02
期刊：
影响因子：
30.8
通讯作者：
Roberts CW
中科院分区：
文献类型：
--
作者：
Mathur R;Alver BH;San Roman AK;Wilson BG;Wang X;Agoston AT;Park PJ;Shivdasani RA;Roberts CW
编码SWI/SNF染色质重塑复合物亚基的基因在约20%的人类癌症中共同突变。虽然ARID 1A是最常见的突变靶点，但其失活促进肿瘤发生的机制尚不清楚。在这里，我们证明了Arid 1a在小鼠结肠中起肿瘤抑制剂的作用，但在小肠中不起作用，并且侵袭性ARID 1A缺陷型腺癌类似于人类结直肠癌（CRC）。这些肿瘤缺乏APC/β-catenin的失调，APC/β-catenin是常见形式的肠癌中的关键守门人。ARID 1A通常将SWI/SNF复合物靶向增强子，在增强子中它们与转录因子（TF）协调起作用以促进基因活化。ARID 1B在ARID 1A缺陷细胞中保留了SWI/SNF功能，但SWI/SNF靶向和增强子活性控制的缺陷导致基因表达的广泛失调。这些发现代表了结肠癌建模的进展，并暗示增强子介导的基因调控是ARID 1A的主要肿瘤抑制功能。
Genes encoding subunits of SWI/SNF chromatin remodeling complexes are collectively mutated in ~20% of all human cancers. Although ARID1A is the most frequent target of mutations, the mechanism by which its inactivation promotes tumorigenesis is unclear. Here, we demonstrate that Arid1a functions as a tumor suppressor in the mouse colon, but not the small intestine, and that invasive ARID1A-deficient adenocarcinomas resemble human colorectal cancer (CRC). These tumors lack deregulation of APC/β-catenin, crucial gatekeepers in common forms of intestinal cancer. ARID1A normally targets SWI/SNF complexes to enhancers, where they function in coordination with transcription factors (TFs) to facilitate gene activation. ARID1B preserves SWI/SNF function in ARID1A-deficient cells, but defects in SWI/SNF targeting and control of enhancer activity cause extensive dysregulation of gene expression. These findings represent an advance in colon cancer modeling and implicate enhancer-mediated gene regulation as a principal tumor suppressor function of ARID1A.