Document Detail


Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase.
MedLine Citation:
PMID:  25253726     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
Stefanie Peter; Jennyfer Bultinck; Kevin Myant; Laura A Jaenicke; Susanne Walz; Judith Müller; Michael Gmachl; Matthias Treu; Guido Boehmelt; Carsten P Ade; Werner Schmitz; Armin Wiegering; Christoph Otto; Nikita Popov; Owen Sansom; Norbert Kraut; Martin Eilers
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-9-24
Journal Detail:
Title:  EMBO molecular medicine     Volume:  -     ISSN:  1757-4684     ISO Abbreviation:  EMBO Mol Med     Publication Date:  2014 Sep 
Date Detail:
Created Date:  2014-9-25     Completed Date:  -     Revised Date:  2014-9-26    
Medline Journal Info:
Nlm Unique ID:  101487380     Medline TA:  EMBO Mol Med     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2014 The Authors. Published under the terms of the CC BY 4.0 license.
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