Transcriptomics,Genomics

Dataset Information

298

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, ARFBP1, 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. MIZ1 and MYC ChIPseq experiments in HUWE1 inhibitor-treated Ls174T cells as well as RNAseq experiments in HUWE1- or MIZ1-depleted Ls174T cells after HUWE1 inhibitor treatment. Sequencing was performed on an Illumina Genome Analyzer IIx.

ORGANISM(S): Homo sapiens  

SUBMITTER: Jennyfer Bultinck   Kevin Myant  Laura A Jaenicke  Martin Eilers  Matthias Treu  Stefanie Peter  Owen Sansom  Guido Boehmelt  Armin Wiegering  Nikita Popov  Judith Müller  Carsten P Ade  Christoph Otto  Werner Schmitz  Michael Gmachl  Susanne Walz  Norbert Kraut 

PROVIDER: E-GEOD-59223 | ArrayExpress | 2014-10-21

SECONDARY ACCESSION(S): GSE59223SRP044171PRJNA254756

REPOSITORIES: GEO, ArrayExpress, ENA

altmetric image

Publications


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  ...[more]

Similar Datasets

2014-10-22 | E-MTAB-1890 | ArrayExpress
2015-07-10 | E-GEOD-59146 | ArrayExpress
2014-07-10 | E-GEOD-44672 | ArrayExpress
2011-11-29 | E-GEOD-18560 | ArrayExpress
2016-01-04 | E-GEOD-70000 | ArrayExpress
2015-10-28 | E-GEOD-66250 | ArrayExpress
2016-08-01 | E-MTAB-3471 | ArrayExpress
2016-01-21 | E-GEOD-64425 | ArrayExpress
2012-01-07 | E-GEOD-34926 | ArrayExpress
2013-09-27 | E-GEOD-48602 | ArrayExpress