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

2.50
Hdl Handle:
http://hdl.handle.net/10541/620140
Title:
HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation.
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
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.
Affiliation:
Cancer Research UK Beatson Institute, Garscube Estate, Bearsden, Glasgow, UK
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
Issue Date:
Feb-2017
URI:
http://hdl.handle.net/10541/620140
DOI:
10.15252/emmm.201606684
PubMed ID:
28003334
Type:
Article
Language:
en
ISSN:
1757-4684
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorMyant, Ken
dc.contributor.authorCammareri, Pen
dc.contributor.authorHodder, Men
dc.contributor.authorWills, Jen
dc.contributor.authorVon Kriegsheim, Aen
dc.contributor.authorGyőrffy, Ben
dc.contributor.authorRashid, Men
dc.contributor.authorPolo, Sen
dc.contributor.authorMaspero, Een
dc.contributor.authorVaughan, Lynseyen
dc.contributor.authorGurung, Ben
dc.contributor.authorBarry, Een
dc.contributor.authorMalliri, Angelikien
dc.contributor.authorCamargo, Fen
dc.contributor.authorAdams, Den
dc.contributor.authorIavarone, Aen
dc.contributor.authorLasorella, Aen
dc.contributor.authorSansom, Oen
dc.date.accessioned2017-02-07T09:51:15Z-
dc.date.available2017-02-07T09:51:15Z-
dc.date.issued2017-02-
dc.identifier.citationHUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation. 2017, 9 (2):181-197 EMBO Mol Meden
dc.identifier.issn1757-4684-
dc.identifier.pmid28003334-
dc.identifier.doi10.15252/emmm.201606684-
dc.identifier.urihttp://hdl.handle.net/10541/620140-
dc.description.abstractCancer 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.en
dc.language.isoenen
dc.rightsArchived with thanks to EMBO molecular medicineen
dc.titleHUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK Beatson Institute, Garscube Estate, Bearsden, Glasgow, UKen
dc.identifier.journalEMBO Molecular Medicineen

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