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

Myant, K. B. et al. (2017) HUWE1 is a critical colonic tumour suppressor gene that prevents MYC signalling, DNA damage accumulation and tumour initiation. EMBO Molecular Medicine, 9(2), pp. 181-197. (doi: 10.15252/emmm.201606684) (PMID:28003334) (PMCID:PMC5286368)

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.

• Item Type: Articles
• Additional Information: All authors are supported by Cancer Research UK. K.B.M. is funded by an AICR grant, a University of Edinburgh Chancellor’s Fellowship and a Cancer Research UK Career Development Fellowship. The research leading to these results has received funding from the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement number 278568.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Myant, Dr Kevin and Cammareri, Dr Patrizia and Von Kriegsheim, Mr Alexander and Sansom, Professor Owen
• Authors: Myant, K. B., Cammareri, P., Hodder, M. C., Wills, J., Von Kriegsheim, A., Győrffy, B., Rashid, M., Polo, S., Maspero, E., Vaughan, L., Gurung, B., Barry, E., Malliri, A., Camargo, F., Adams, D. J., Iavarone, A., Lasorella, A., and Sansom, O. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: EMBO Molecular Medicine
• Publisher: Wiley for EMBO Press
• ISSN: 1757-4676
• ISSN (Online): 1757-4684
• Published Online: 21 December 2016
• Copyright Holders: Copyright © 2016 Cancer Research UK Beatson Institute
• First Published: First published in EMBO Molecular Medicine 9(2):181-197
• Publisher Policy: Reproduced under a creative commons license