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H Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase

Please always quote using this URN: urn:nbn:de:bvb:20-opus-118132
  • 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 colonDeregulated 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.show moreshow less

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Metadaten
Author: Stefanie Peter, Jennyfer Bultinck, Kevin Myant, Laura A. Jaenicke, Susanne Walz, Judith Müller, Michael Gmachl, Matthias Treu, Guido Boehmelt, Casten P. Ade, Werner Schmitz, Armin Wiegering, Christoph Otto, Nikita Popov, Owen Sansom, Norbert Kraut, Martin Eilers
URN:urn:nbn:de:bvb:20-opus-118132
Document Type:Journal article
Faculties:Medizinische Fakultät / Theodor-Boveri-Institut für Biowissenschaften
Language:English
Parent Title (English):EMBO Molecular Medicine
ISSN:1757-4684
Year of Completion:2014
Volume:6
Issue:12
Pagenumber:1525-41
Source:EMBO Mololecular Medicine (2014) 6: 1525–1541. DOI 10.15252/emmm.201403927
DOI:https://doi.org/10.15252/emmm.201403927
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 571 Physiologie und verwandte Themen
Tag:HUWE1; MIZ1; MYC; cancer; colorectal cancer; digestive system; drug discovery; pharmacology; ubiquitination
Release Date:2015/09/04
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung