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

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...

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Autores principales: Myant, Kevin B, Cammareri, Patrizia, Hodder, Michael C, Wills, Jimi, Von Kriegsheim, Alex, Győrffy, Balázs, Rashid, Mamun, Polo, Simona, Maspero, Elena, Vaughan, Lynsey, Gurung, Basanta, Barry, Evan, Malliri, Angeliki, Camargo, Fernando, Adams, David J, Iavarone, Antonio, Lasorella, Anna, Sansom, Owen J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5286368/
https://www.ncbi.nlm.nih.gov/pubmed/28003334
http://dx.doi.org/10.15252/emmm.201606684
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author Myant, Kevin B
Cammareri, Patrizia
Hodder, Michael C
Wills, Jimi
Von Kriegsheim, Alex
Győrffy, Balázs
Rashid, Mamun
Polo, Simona
Maspero, Elena
Vaughan, Lynsey
Gurung, Basanta
Barry, Evan
Malliri, Angeliki
Camargo, Fernando
Adams, David J
Iavarone, Antonio
Lasorella, Anna
Sansom, Owen J
author_facet Myant, Kevin B
Cammareri, Patrizia
Hodder, Michael C
Wills, Jimi
Von Kriegsheim, Alex
Győrffy, Balázs
Rashid, Mamun
Polo, Simona
Maspero, Elena
Vaughan, Lynsey
Gurung, Basanta
Barry, Evan
Malliri, Angeliki
Camargo, Fernando
Adams, David J
Iavarone, Antonio
Lasorella, Anna
Sansom, Owen J
author_sort Myant, Kevin B
collection PubMed
description 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.
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spelling pubmed-52863682017-02-03 HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation Myant, Kevin B Cammareri, Patrizia Hodder, Michael C Wills, Jimi Von Kriegsheim, Alex Győrffy, Balázs Rashid, Mamun Polo, Simona Maspero, Elena Vaughan, Lynsey Gurung, Basanta Barry, Evan Malliri, Angeliki Camargo, Fernando Adams, David J Iavarone, Antonio Lasorella, Anna Sansom, Owen J EMBO Mol Med Research Articles 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. John Wiley and Sons Inc. 2016-12-22 2017-02 /pmc/articles/PMC5286368/ /pubmed/28003334 http://dx.doi.org/10.15252/emmm.201606684 Text en © 2016 Cancer Research UK Beatson Institute. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Myant, Kevin B
Cammareri, Patrizia
Hodder, Michael C
Wills, Jimi
Von Kriegsheim, Alex
Győrffy, Balázs
Rashid, Mamun
Polo, Simona
Maspero, Elena
Vaughan, Lynsey
Gurung, Basanta
Barry, Evan
Malliri, Angeliki
Camargo, Fernando
Adams, David J
Iavarone, Antonio
Lasorella, Anna
Sansom, Owen J
HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation
title HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation
title_full HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation
title_fullStr HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation
title_full_unstemmed HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation
title_short HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation
title_sort huwe1 is a critical colonic tumour suppressor gene that prevents myc signalling, dna damage accumulation and tumour initiation
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5286368/
https://www.ncbi.nlm.nih.gov/pubmed/28003334
http://dx.doi.org/10.15252/emmm.201606684
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