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  - Otto, Christoph
A1  - Kastner, Carolin
A1  - Schmidt, Stefanie
A1  - Uttinger, Konstantin
A1  - Baluapuri, Apoorva
A1  - Denk, Sarah
A1  - Rosenfeldt, Mathias T.
A1  - Rosenwald, Andreas
A1  - Roehrig, Florian
A1  - Ade, Carsten P.
A1  - Schuelein-Voelk, Christina
A1  - Diefenbacher, Markus E.
A1  - Germer, Christoph-Thomas
A1  - Wolf, Elmar
A1  - Eilers, Martin
A1  - Wiegering, Armin
T1  - RNA polymerase I inhibition induces terminal differentiation, growth arrest, and vulnerability to senolytics in colorectal cancer cells
JF  - Molecular Oncology
N2  - Ribosomal biogenesis and protein synthesis are deregulated in most cancers, suggesting that interfering with translation machinery may hold significant therapeutic potential. Here, we show that loss of the tumor suppressor adenomatous polyposis coli (APC), which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces the expression of RNA polymerase I (RNAPOL1) transcription machinery, and subsequently upregulates ribosomal DNA (rDNA) transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity, and induces a disbalance of ribosomal proteins. Surprisingly, CX5461-induced growth arrest is irreversible and exhibits features of senescence and terminal differentiation. Mechanistically, CX5461 promotes differentiation in an MYC-interacting zinc-finger protein 1 (MIZ1)- and retinoblastoma protein (Rb)-dependent manner. In addition, the inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. We validated this therapeutic effect of CX5461 in murine- and patient-derived organoids, and in a xenograft mouse model. These results show that targeting ribosomal biogenesis together with targeting the consecutive, senescent phenotype using approved drugs is a new therapeutic approach, which can rapidly be transferred from bench to bedside.
KW  - CRC
KW  - CX5461
KW  - MIZ1
KW  - MYC
KW  - ribosome
KW  - RNAPOL1
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312806
VL  - 16
IS  - 15
ER  -