title: HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation.
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.
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Bearsden, Glasgow, UK kevin.myant@igmm.ed.ac.uk o.sansom@beatson.gla.ac.uk.|Cancer Research UK Edinburgh Centre, The Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors.forename: Kevin B
authors.identifier: 0000-0001-8017-1093
authors.initials: KB
authors.lastname: Myant
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Bearsden, Glasgow, UK.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Cammareri
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Bearsden, Glasgow, UK.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Hodder
authors.affiliation: Cancer Research UK Edinburgh Centre, The Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors.forename: Jimi
authors.initials: J
authors.lastname: Wills
authors.affiliation: Cancer Research UK Edinburgh Centre, The Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Von Kriegsheim
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.|2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Mamun
authors.initials: M
authors.lastname: Rashid
authors.affiliation: IFOM, The FIRC Institute for Molecular Oncology, Milano, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Polo
authors.affiliation: IFOM, The FIRC Institute for Molecular Oncology, Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Maspero
authors.affiliation: Cancer Research UK Manchester Institute, The University of Manchester, Withington, Manchester, UK.
authors.forename: Lynsey
authors.initials: L
authors.lastname: Vaughan
authors.affiliation: Boston Children's Hospital, Boston, MA, USA.
authors.forename: Basanta
authors.initials: B
authors.lastname: Gurung
authors.affiliation: Boston Children's Hospital, Boston, MA, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Barry
authors.affiliation: Cancer Research UK Manchester Institute, The University of Manchester, Withington, Manchester, UK.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Malliri
authors.affiliation: Boston Children's Hospital, Boston, MA, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Camargo
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: Departments of Neurology and Pathology, Institute for Cancer Genetics, Irving Comprehensive Research Center, New York, NY, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Iavarone
authors.affiliation: Departments of Pediatrics and Pathology, Institute for Cancer Genetics, Irving Comprehensive Research Center, New York, NY, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Lasorella
authors.affiliation: Cancer Research UK Beatson Institute, Garscube Estate, Bearsden, Glasgow, UK kevin.myant@igmm.ed.ac.uk o.sansom@beatson.gla.ac.uk.
authors.forename: Owen J
authors.identifier: 0000-0001-9540-3010
authors.initials: OJ
authors.lastname: Sansom
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D015179:Colorectal Neoplasms / Q000473:pathology*; D004249:DNA Damage; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins; C502831:Huwe1 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: 
  MYC
  ; DNA damage; HUWE1; MCL1; colorectal cancer