Tumor cell‐specific inhibition of MYC function using small molecule inhibitors of the HUWE 1 ubiquitin ligase

Peter, S. et al. (2014) Tumor cell‐specific inhibition of MYC function using small molecule inhibitors of the HUWE 1 ubiquitin ligase. EMBO Molecular Medicine, 6(12), pp. 1525-1541. (doi:10.15252/emmm.201403927) (PMID:25253726) (PMCID:PMC4287973)

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Abstract

Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF‐BP1, MULE) associates with both MYC and the MYC‐associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high‐throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC‐dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC‐activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Myant, Dr Kevin and Sansom, Professor Owen
Authors: Peter, S., Bultinck, J., Myant, K., Jaenicke, L. A., Walz, S., Müller, J., Gmachl, M., Treu, M., Boehmelt, G., Ade, C. P., Schmitz, W., Wiegering, A., Otto, C., Popov, N., Sansom, O., Kraut, N., and Eilers, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:EMBO Molecular Medicine
Publisher:EMBO Press
ISSN:1757-4676
ISSN (Online):1757-4684
Published Online:24 September 2014
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in EMBO Molecular Medicine 6(12):1525-1541
Publisher Policy:Reproduced under a Creative Commons license

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