title: Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase.
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.
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Peter
authors.affiliation: Cytokine Receptor Lab, Department of Biochemistry, Ghent University, Ghent, Belgium.
authors.forename: Jennyfer
authors.initials: J
authors.lastname: Bultinck
authors.affiliation: CRUK Beatson Institute, Glasgow, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Myant
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Jaenicke
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Walz
authors.affiliation: Department of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Judith
authors.initials: J
authors.lastname: Müller
authors.affiliation: Department Lead Discovery, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Gmachl
authors.affiliation: Department Lead Discovery, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Treu
authors.affiliation: Department Lead Discovery, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors.forename: Guido
authors.initials: G
authors.lastname: Boehmelt
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Carsten P
authors.initials: CP
authors.lastname: Ade
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Schmitz
authors.affiliation: Department of General, Visceral, Vascular and Paediatric Surgery, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Wiegering
authors.affiliation: Department of General, Visceral, Vascular and Paediatric Surgery, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Otto
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
authors.forename: Nikita
authors.initials: N
authors.lastname: Popov
authors.affiliation: CRUK Beatson Institute, Glasgow, UK.
authors.forename: Owen
authors.initials: O
authors.lastname: Sansom
authors.affiliation: Department Lead Discovery, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors.forename: Norbert
authors.initials: N
authors.lastname: Kraut
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Würzburg, Germany Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany martin.eilers@biozentrum.uni-wuerzburg.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D016274:Oncogene Protein p55(v-myc) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000494:pharmacology*; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D051741:Kruppel-Like Transcription Factors; D016274:Oncogene Protein p55(v-myc); D054852:Small Molecule Libraries; D025521:Tumor Suppressor Proteins; C107961:ZBTB17 protein, human; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: HUWE1; MIZ1; MYC; colorectal cancer; ubiquitination