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    HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation.

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    Authors
    Myant, K
    Cammareri, P
    Hodder, M
    Wills, J
    Von Kriegsheim, A
    Győrffy, B
    Rashid, M
    Polo, S
    Maspero, E
    Vaughan, Lynsey
    Gurung, B
    Barry, E
    Malliri, Angeliki
    Camargo, F
    Adams, D
    Iavarone, A
    Lasorella, A
    Sansom, O
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    Affiliation
    Cancer Research UK Beatson Institute, Garscube Estate, Bearsden, Glasgow, UK
    Issue Date
    2017-02
    
    Metadata
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    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.
    Citation
    HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation. 2017, 9 (2):181-197 EMBO Mol Med
    Journal
    EMBO Molecular Medicine
    URI
    http://hdl.handle.net/10541/620140
    DOI
    10.15252/emmm.201606684
    PubMed ID
    28003334
    Type
    Article
    Language
    en
    ISSN
    1757-4684
    ae974a485f413a2113503eed53cd6c53
    10.15252/emmm.201606684
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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