TY  - JOUR
A1  - Lorenzin, Francesca
A1  - Benary, Uwe
A1  - Baluapuri, Apoorva
A1  - Walz, Susanne
A1  - Jung, Lisa Anna
A1  - von Eyss, Björn
A1  - Kisker, Caroline
A1  - Wolf, Jana
A1  - Eilers, Martin
A1  - Wolf, Elmar
T1  - Different promoter affinities account for specificity in MYC-dependent gene regulation
JF  - eLife
N2  - Enhanced expression of the MYC transcription factor is observed in the majority of tumors. Two seemingly conflicting models have been proposed for its function: one proposes that MYC enhances expression of all genes, while the other model suggests gene-specific regulation. Here, we have explored the hypothesis that specific gene expression profiles arise since promoters differ in affinity for MYC and high-affinity promoters are fully occupied by physiological levels of MYC. We determined cellular MYC levels and used RNA- and ChIP-sequencing to correlate promoter occupancy with gene expression at different concentrations of MYC. Mathematical modeling showed that binding affinities for interactions of MYC with DNA and with core promoter-bound factors, such as WDR5, are sufficient to explain promoter occupancies observed in vivo. Importantly, promoter affinity stratifies different biological processes that are regulated by MYC, explaining why tumor-specific MYC levels induce specific gene expression programs and alter defined biological properties of cells.
KW  - MYC
KW  - promoter affinity
KW  - human
KW  - mathematical modeling
KW  - mouse
KW  - ChIP-sequencing
KW  - MIZ1
KW  - cancer biology
KW  - cell biology
KW  - WDR5
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162913
VL  - 5
ER  - 
TY  - JOUR
A1  - Peter, Stefanie
A1  - Bultinck, Jennyfer
A1  - Myant, Kevin
A1  - Jaenicke, Laura A.
A1  - Walz, Susanne
A1  - Müller, Judith
A1  - Gmachl, Michael
A1  - Treu, Matthias
A1  - Boehmelt, Guido
A1  - Ade, Casten P.
A1  - Schmitz, Werner
A1  - Wiegering, Armin
A1  - Otto, Christoph
A1  - Popov, Nikita
A1  - Sansom, Owen
A1  - Kraut, Norbert
A1  - Eilers, Martin
T1  - H Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase
JF  - EMBO Molecular Medicine
N2  - 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.
KW  - colorectal cancer
KW  - HUWE1
KW  - MIZ1
KW  - MYC
KW  - ubiquitination
KW  - cancer
KW  - digestive system
KW  - pharmacology
KW  - drug discovery
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118132
SN  - 1757-4684
VL  - 6
IS  - 12
ER  - 
TY  - JOUR
A1  - Prieto‐Garcia, Cristian
A1  - Hartmann, Oliver
A1  - Reissland, Michaela
A1  - Braun, Fabian
A1  - Fischer, Thomas
A1  - Walz, Susanne
A1  - Schülein‐Völk, Christina
A1  - Eilers, Ursula
A1  - Ade, Carsten P.
A1  - Calzado, Marco A.
A1  - Orian, Amir
A1  - Maric, Hans M.
A1  - Münch, Christian
A1  - Rosenfeldt, Mathias
A1  - Eilers, Martin
A1  - Diefenbacher, Markus E.
T1  - Maintaining protein stability of ∆Np63 via USP28 is required by squamous cancer cells
JF  - EMBO Molecular Medicine
N2  - The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome‐mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9‐engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours.
KW  - ∆Np63
KW  - NOTCH
KW  - squamous cell carcinoma
KW  - 28
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218303
VL  - 12
IS  - 4
ER  -