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

• Published in: EMBO molecular medicine Vol. 6; no. 12; pp. 1525 - 1541
• Main Authors: Peter, Stefanie, Bultinck, Jennyfer, Myant, Kevin, Jaenicke, Laura A, Walz, Susanne, Müller, Judith, Gmachl, Michael, Treu, Matthias, Boehmelt, Guido, Ade, Carsten P, Schmitz, Werner, Wiegering, Armin, Otto, Christoph, Popov, Nikita, Sansom, Owen, Kraut, Norbert, Eilers, Martin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2014; John Wiley & Sons, Inc; EMBO Press; BlackWell Publishing Ltd; Springer Nature
• Subjects: Animals; Cancer; Carcinogenesis; Cell culture; Cell Line, Tumor; Cell Proliferation; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - genetics; Colorectal Neoplasms - physiopathology; EMBO03; EMBO12; EMBO28; Epithelial cells; Experiments; Gene expression; Gene Expression Regulation, Neoplastic; Gene silencing; Genetic transcription; Humans; HUWE1; Huwe1 protein; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Laboratories; Ligases; Mice; Mice, SCID; MIZ1; MYC; Myc protein; Oncogene Protein p55(v-myc) - antagonists & inhibitors; Oncogene Protein p55(v-myc) - genetics; Oncogene Protein p55(v-myc) - metabolism; Protein Binding; Proteins; Research Article; Signal transduction; Small Molecule Libraries - administration & dosage; Small Molecule Libraries - pharmacology; Stem cells; Transcription activation; Transcriptional Activation; Tumor cells; Tumor Suppressor Proteins; Tumorigenesis; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - antagonists & inhibitors; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; ubiquitination; Xenografts; HUWE1; colorectal cancer; ubiquitination; MYC; MIZ1
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.201403927

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. Synopsis New highly specific inhibitors of HUWE1 have been identified that can inhibit MYC function in a tumour cell‐specific manner, by preventing the HUWE1‐mediated block of a repressive complex of MYC with MIZ1 on MYC‐activated target genes. HUWE1 is essential for growth of colorectal tumors in vivo and is globally required for expression of MYC target genes. Small‐molecule inhibitors of HUWE1 inhibit expression of MYC target genes in a tumor‐cell specific manner. Inhibition of HUWE1 stabilizes MIZ1 and induces global accumulation of MIZ1 on MYC‐bound target genes. Accumulation of MIZ1 is required for repression of ribosomal protein genes upon HUWE1 inhibition. Graphical Abstract New highly specific inhibitors of HUWE1 have been identified that can inhibit MYC function in a tumour cell‐specific manner, by preventing the HUWE1‐mediated block of a repressive complex of MYC with MIZ1 on MYC‐activated target genes.