@article{KunzBommertKruketal.2020,
  author    = {Kunz, Viktoria and Bommert, Kathryn S. and Kruk, Jessica and Schwinning, Daniel and Chatterjee, Manik and St{\"u}hmer, Thorsten and Bargou, Ralf and Bommert, Kurt},
  title     = {Targeting of the E3 ubiquitin-protein ligase HUWE1 impairs DNA repair capacity and tumor growth in preclinical multiple myeloma models},
  series = {Scientific Reports},
  volume    = {10},
  journal   = {Scientific Reports},
  doi       = {10.1038/s41598-020-75499-3},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230632},
  year      = {2020},
  abstract  = {Experimental evidence suggests that ubiquitin-protein ligases regulate a number of cellular processes involved in tumorigenesis. We analysed the role of the E3 ubiquitin-protein ligase HUWE1 for pathobiology of multiple myeloma (MM), a still incurable blood cancer. mRNA expression analysis indicates an increase in HUWE1 expression levels correlated with advanced stages of myeloma. Pharmacologic as well as RNAi-mediated HUWE1 inhibition caused anti-proliferative effects in MM cell lines in vitro and in an MM1.S xenotransplantation mouse model. Cell cycle analysis upon HUWE1 inhibition revealed decreased S phase cell fractions. Analyses of potential HUWE1-dependent molecular functions did not show involvement in MYC-dependent gene regulation. However, HUWE1 depleted MM cells displayed increased DNA tail length by comet assay, as well as changes in the levels of DNA damage response mediators such as pBRCA1, DNA-polymerase beta, gamma H2AX and Mcl-1. Our finding that HUWE1 might thus be involved in endogenous DNA repair is further supported by strongly enhanced apoptotic effects of the DNA-damaging agent melphalan in HUWE1 depleted cells in vitro and in vivo. These data suggest that HUWE1 might contribute to tumour growth by endogenous repair of DNA, and could therefore potentially be exploitable in future treatment developments.},
  language  = {en}
}
@article{OttoKastnerSchmidtetal.2022,
  author    = {Otto, Christoph and Kastner, Carolin and Schmidt, Stefanie and Uttinger, Konstantin and Baluapuri, Apoorva and Denk, Sarah and Rosenfeldt, Mathias T. and Rosenwald, Andreas and Roehrig, Florian and Ade, Carsten P. and Schuelein-Voelk, Christina and Diefenbacher, Markus E. and Germer, Christoph-Thomas and Wolf, Elmar and Eilers, Martin and Wiegering, Armin},
  title     = {RNA polymerase I inhibition induces terminal differentiation, growth arrest, and vulnerability to senolytics in colorectal cancer cells},
  series = {Molecular Oncology},
  volume    = {16},
  journal   = {Molecular Oncology},
  number    = {15},
  doi       = {10.1002/1878-0261.13265},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312806},
  pages     = {2788-2809},
  year      = {2022},
  abstract  = {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.},
  language  = {en}
}
@article{HartmannReisslandMaieretal.2021,
  author    = {Hartmann, Oliver and Reissland, Michaela and Maier, Carina R. and Fischer, Thomas and Prieto-Garcia, Cristian and Baluapuri, Apoorva and Schwarz, Jessica and Schmitz, Werner and Garrido-Rodriguez, Martin and Pahor, Nikolett and Davies, Clare C. and Bassermann, Florian and Orian, Amir and Wolf, Elmar and Schulze, Almut and Calzado, Marco A. and Rosenfeldt, Mathias T. and Diefenbacher, Markus E.},
  title     = {Implementation of CRISPR/Cas9 Genome Editing to Generate Murine Lung Cancer Models That Depict the Mutational Landscape of Human Disease},
  series = {Frontiers in Cell and Developmental Biology},
  volume    = {9},
  journal   = {Frontiers in Cell and Developmental Biology},
  issn      = {2296-634X},
  doi       = {10.3389/fcell.2021.641618},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230949},
  year      = {2021},
  abstract  = {Lung cancer is the most common cancer worldwide and the leading cause of cancer-related deaths in both men and women. Despite the development of novel therapeutic interventions, the 5-year survival rate for non-small cell lung cancer (NSCLC) patients remains low, demonstrating the necessity for novel treatments. One strategy to improve translational research is the development of surrogate models reflecting somatic mutations identified in lung cancer patients as these impact treatment responses. With the advent of CRISPR-mediated genome editing, gene deletion as well as site-directed integration of point mutations enabled us to model human malignancies in more detail than ever before. Here, we report that by using CRISPR/Cas9-mediated targeting of Trp53 and KRas, we recapitulated the classic murine NSCLC model Trp53fl/fl:lsl-KRasG12D/wt. Developing tumors were indistinguishable from Trp53fl/fl:lsl-KRasG12D/wt-derived tumors with regard to morphology, marker expression, and transcriptional profiles. We demonstrate the applicability of CRISPR for tumor modeling in vivo and ameliorating the need to use conventional genetically engineered mouse models. Furthermore, tumor onset was not only achieved in constitutive Cas9 expression but also in wild-type animals via infection of lung epithelial cells with two discrete AAVs encoding different parts of the CRISPR machinery. While conventional mouse models require extensive husbandry to integrate new genetic features allowing for gene targeting, basic molecular methods suffice to inflict the desired genetic alterations in vivo. Utilizing the CRISPR toolbox, in vivo cancer research and modeling is rapidly evolving and enables researchers to swiftly develop new, clinically relevant surrogate models for translational research.},
  language  = {en}
}
@article{PeterBultinckMyantetal.2014,
  author    = {Peter, Stefanie and Bultinck, Jennyfer and Myant, Kevin and Jaenicke, Laura A. and Walz, Susanne and M{\"u}ller, Judith and Gmachl, Michael and Treu, Matthias and Boehmelt, Guido and Ade, Casten P. and Schmitz, Werner and Wiegering, Armin and Otto, Christoph and Popov, Nikita and Sansom, Owen and Kraut, Norbert and Eilers, Martin},
  title     = {H Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase},
  series = {EMBO Molecular Medicine},
  volume    = {6},
  journal   = {EMBO Molecular Medicine},
  number    = {12},
  issn      = {1757-4684},
  doi       = {10.15252/emmm.201403927},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118132},
  pages     = {1525-41},
  year      = {2014},
  abstract  = {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.},
  language  = {en}
}
@article{EffenbergerBommertKunzetal.2017,
  author    = {Effenberger, Madlen and Bommert, Kathryn S. and Kunz, Viktoria and Kruk, Jessica and Leich, Ellen and Rudelius, Martina and Bargou, Ralf and Bommert, Kurt},
  title     = {Glutaminase inhibition in multiple myeloma induces apoptosis via MYC degradation},
  series = {Oncotarget},
  volume    = {8},
  journal   = {Oncotarget},
  number    = {49},
  doi       = {10.18632/oncotarget.20691},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170168},
  pages     = {85858-85867},
  year      = {2017},
  abstract  = {Multiple Myeloma (MM) is an incurable hematological malignancy affecting millions of people worldwide. As in all tumor cells both glucose and more recently glutamine have been identified as important for MM cellular metabolism, however there is some dispute as to the role of glutamine in MM cell survival. Here we show that the small molecule inhibitor compound 968 effectively inhibits glutaminase and that this inhibition induces apoptosis in both human multiple myeloma cell lines (HMCLs) and primary patient material. The HMCL U266 which does not express MYC was insensitive to both glutamine removal and compound 968, but ectopic expression of MYC imparted sensitivity. Finally, we show that glutamine depletion is reflected by rapid loss of MYC protein which is independent of MYC transcription and post translational modifications. However, MYC loss is dependent on proteasomal activity, and this loss was paralleled by an equally rapid induction of apoptosis. These findings are in contrast to those of glucose depletion which largely affected rates of proliferation in HMCLs, but had no effects on either MYC expression or viability. Therefore, inhibition of glutaminolysis is effective at inducing apoptosis and thus serves as a possible therapeutic target in MM.},
  language  = {en}
}
@article{LorenzinBenaryBaluapurietal.2016,
  author    = {Lorenzin, Francesca and Benary, Uwe and Baluapuri, Apoorva and Walz, Susanne and Jung, Lisa Anna and von Eyss, Bj{\"o}rn and Kisker, Caroline and Wolf, Jana and Eilers, Martin and Wolf, Elmar},
  title     = {Different promoter affinities account for specificity in MYC-dependent gene regulation},
  series = {eLife},
  volume    = {5},
  journal   = {eLife},
  doi       = {10.7554/eLife.15161},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-162913},
  pages     = {e15161},
  year      = {2016},
  abstract  = {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.},
  language  = {en}
}
@article{BerendzenWeisteWankeetal.2012,
  author    = {Berendzen, Kenneth W. and Weiste, Christoph and Wanke, Dierk and Kilian, Joachim and Harter, Klaus and Dr{\"o}ge-Laser, Wolfgang},
  title     = {Bioinformatic cis-element analyses performed in Arabidopsis and rice disclose bZIP- and MYB-related binding sites as potential AuxRE-coupling elements in auxin-mediated transcription},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75138},
  year      = {2012},
  abstract  = {Background: In higher plants, a diverse array of developmental and growth-related processes is regulated by the plant hormone auxin. Recent publications have proposed that besides the well-characterized Auxin Response Factors (ARFs) that bind Auxin Response Elements (AuxREs), also members of the bZIP- and MYB-transcription factor (TF) families participate in transcriptional control of auxin-regulated genes via bZIP Response Elements (ZREs) or Myb Response Elements (MREs), respectively. Results: Applying a novel bioinformatic algorithm, we demonstrate on a genome-wide scale that singular motifs or composite modules of AuxREs, ZREs, MREs but also of MYC2 related elements are significantly enriched in promoters of auxin-inducible genes. Despite considerable, species-specific differences in the genome structure in terms of the GC content, this enrichment is generally conserved in dicot (Arabidopsis thaliana) and monocot (Oryza sativa) model plants. Moreover, an enrichment of defined composite modules has been observed in selected auxin-related gene families. Consistently, a bipartite module, which encompasses a bZIP-associated G-box Related Element (GRE) and an AuxRE motif, has been found to be highly enriched. Making use of transient reporter studies in protoplasts, these findings were experimentally confirmed, demonstrating that GREs functionally interact with AuxREs in regulating auxin-mediated transcription. Conclusions: Using genome-wide bioinformatic analyses, evolutionary conserved motifs have been defined which potentially function as AuxRE-dependent coupling elements to establish auxin-specific expression patterns. Based on these findings, experimental approaches can be designed to broaden our understanding of combinatorial, auxin-controlled gene regulation.},
  subject      = {Arabidopsis},
  language  = {en}
}