Abstract
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.
Highlights
Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance
HUWE1 is a pleiotropic E3 ubiquitin ligase that modulates the function of several proteins involved in oncogenesis and DNA damage response including MYC, MYCN, MCL1 and H2AX (Adhikary et al, 2005; Zhong et al, 2005; Zhao et al, 2008; de Groot et al, 2014)
Huwe1 was identified as a high-ranking positive hit in a Colorectal cancer (CRC) transposon mutagenesis screen indicating its mutation may be important to colorectal tumourigenic, but to date direct functional determination of this is lacking (March et al, 2011)
Summary
Cancer genome sequencing projects have identified hundreds of genetic alterations, often at low frequencies, raising questions as to their functional relevance. Genetic deletion of Huwe rapidly accelerated tumourigenic in mice carrying loss of the intestinal tumour suppressor gene Apc, with a dramatic increase in tumour initiation. 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 Huwe1deficient tumours to DNA-damaging agents and to deletion of the anti-apoptotic protein MCL1. The increased levels of DNA damage sensitised Huwe1deficient 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
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