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  - Jessen, Christina
A1  - Kreß, Julia K. C.
A1  - Baluapuri, Apoorva
A1  - Hufnagel, Anita
A1  - Schmitz, Werner
A1  - Kneitz, Susanne
A1  - Roth, Sabine
A1  - Marquardt, André
A1  - Appenzeller, Silke
A1  - Ade, Casten P.
A1  - Glutsch, Valerie
A1  - Wobser, Marion
A1  - Friedmann-Angeli, José Pedro
A1  - Mosteo, Laura
A1  - Goding, Colin R.
A1  - Schilling, Bastian
A1  - Geissinger, Eva
A1  - Wolf, Elmar
A1  - Meierjohann, Svenja
T1  - The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression
JF  - Oncogene
N2  - The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H\(_2\)O\(_2\) or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.
KW  - NRF2
KW  - melanoma malignancy
KW  - COX2 expression
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235064
SN  - 0950-9232
VL  - 39
ER  -