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.
HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation / K.B. Myant, P. Cammareri, M.C. Hodder, J. Wills, A. Von Kriegsheim, B. Győrffy, M. Rashid, S. Polo, E. Maspero, L. Vaughan, B. Gurung, E. Barry, A. Malliri, F. Camargo, D.J. Adams, A. Iavarone, A. Lasorella, O.J. Sansom. - In: EMBO MOLECULAR MEDICINE. - ISSN 1757-4676. - 9:2(2017 Feb), pp. 181-197.
|Titolo:||HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation|
|Parole Chiave:||colorectal cancer; DNA damage; HUWE1; MCL1; MYC; Molecular Medicine|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||feb-2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.15252/emmm.201606684|
|Appare nelle tipologie:||01 - Articolo su periodico|