BI8626

Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE 1 ( HECTH 9, ARF ‐ BP 1, MULE ) associates with both MYC and the MYC ‐associated protein MIZ 1. We show here that HUWE 1 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 HUWE 1, which inhibit MYC ‐dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE 1 stabilizes MIZ 1. MIZ 1 globally accumulates on MYC target genes and contributes to repression of MYC ‐activated target genes upon HUWE 1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ 1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.