2. Academic Validation
  3. Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase

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

  • EMBO Mol Med. 2014 Dec;6(12):1525-41. doi: 10.15252/emmm.201403927.
Stefanie Peter 1,  Jennyfer Bultinck 2,  Kevin Myant 3,  Laura A Jaenicke 1,  Susanne Walz 1,  Judith Müller 4,  Michael Gmachl 5,  Matthias Treu 5,  Guido Boehmelt 5,  Carsten P Ade 1,  Werner Schmitz 1,  Armin Wiegering 6,  Christoph Otto 6,  Nikita Popov 7,  Owen Sansom 3,  Norbert Kraut 5,  Martin Eilers 8
Affiliations

Affiliations

  • 1 Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany.
  • 2 Cytokine Receptor Lab, Department of Biochemistry, Ghent University, Ghent, Belgium.
  • 3 CRUK Beatson Institute, Glasgow, UK.
  • 4 Department of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 5 Department Lead Discovery, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
  • 6 Department of General, Visceral, Vascular and Paediatric Surgery, University Hospital Würzburg, Würzburg, Germany.
  • 7 Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
  • 8 Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany [email protected].
PMID: 25253726 DOI: 10.15252/emmm.201403927
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.

Keywords

HUWE1; MIZ1; MYC; colorectal cancer; ubiquitination.

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