HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation.
HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation.
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DOI：
10.15252/emmm.201606684
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发表时间：
2017-02
影响因子：
11.1
通讯作者：
Sansom OJ
中科院分区：
文献类型：
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作者：
Myant KB;Cammareri P;Hodder MC;Wills J;Von Kriegsheim A;Győrffy B;Rashid M;Polo S;Maspero E;Vaughan L;Gurung B;Barry E;Malliri A;Camargo F;Adams DJ;Iavarone A;Lasorella A;Sansom OJ
癌症基因组测序项目已经确定了数百种基因改变，通常频率很低，这就对其功能相关性提出了质疑。一个典型的基因是HUWE1，在许多研究中发现它发生了突变。然而，由于该基因的大尺寸和鉴定的突变的功能分析的缺乏，它们的致癌意义尚不清楚。为了确定HUWE1的重要性，我们选择检查其在结直肠癌中的功能，其中高达15%的肿瘤发生突变。对所鉴定的突变的建模表明，它们破坏HUWE1的E3泛素连接酶活性。Huwe1的基因缺失在携带肠道肿瘤抑制基因Apc缺失的小鼠中迅速加速肿瘤发生，肿瘤起始急剧增加。从机制上讲，这种表型是由MYC增加和DNA损伤快速积累导致Apc第二拷贝丢失驱动的。DNA损伤水平的增加使Huwe1缺陷型肿瘤对DNA损伤剂和抗凋亡蛋白MCL1的缺失敏感。总之，这些数据将HUWE1鉴定为肠上皮中真正的肿瘤抑制基因，并表明HUWE1突变肿瘤对DNA损伤剂和抗凋亡蛋白抑制剂的潜在脆弱性。
Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. One exemplar gene is HUWE1, which has been found to be mutated in numerous studies. However, due to the large size of this gene and a lack of functional analysis of identified mutations, their significance to carcinogenesis is unclear. To determine the importance of HUWE1, we chose to examine its function in colorectal cancer, where it is mutated in up to 15 per cent of tumours. Modelling of identified mutations showed that they inactivate the E3 ubiquitin ligase activity of HUWE1. Genetic deletion of Huwe1 rapidly accelerated tumourigenic in mice carrying loss of the intestinal tumour suppressor gene Apc, with a dramatic increase in tumour initiation. Mechanistically, this phenotype was driven by increased MYC and rapid DNA damage accumulation leading to loss of the second copy of Apc. The increased levels of DNA damage sensitised Huwe1‐deficient tumours to DNA‐damaging agents and to deletion of the anti‐apoptotic protein MCL1. Taken together, these data identify HUWE1 as a bona fide tumour suppressor gene in the intestinal epithelium and suggest a potential vulnerability of HUWE1‐mutated tumours to DNA‐damaging agents and inhibitors of anti‐apoptotic proteins.