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  • American Association for Cancer Research (AACR)  (3)
  • 1
    Online Resource
    Online Resource
    Abstract 3138: IL-6/Stat3 signaling is an indispensable modulator of oncogene-induced cellular senescence
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3138-3138
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3138-3138
    Abstract: IL-6/Stat3 signaling plays a role as a proto-oncogene in various tumors including prostate cancer, where IL-6 has been explored as therapeutic target. Deficiency of Pten, one of the most commonly mutated genes in cancer, directly triggers a senescence program critically depending on the p19Arf-p53 fail-safe pathway. We identified a novel and unexpected tumor suppressive role of IL-6/Stat3 signaling in a Pten-deficient murine prostate cancer model. Our data provide evidence that activation of IL-6/Stat3 signaling axis is implicated in oncogene-induced senescence (OIS). Strikingly, genetic ablation of IL-6 strongly promoted prostate cancer initiation, progression and metastasis in Pten-deficient mice. Mechanistically, IL6/Stat3 signaling regulates p19Arf-p53-induced senescence by modulating expression of the ubiquitin ligase MDM2 in pre-neoplastic cells. Critically, in prostate cancer patients low expression of Stat3 or p14Arf, the human homologue of p19Arf, correlates with poor survival. Therefore, the IL-6/Stat3 signaling axis may represent a novel molecular target for senescence-based cancer therapies. Citation Format: Jan Pencik, Michaela Schlederer, Melanie Hassler, Wolfgang Gruber, Fritz Aberger, Richard Kennedy, Stephen Walker, Stephan Rose-John, Valeria Poli, Robert Eferl, Harald Esterbauer, Osman Aksoy, Merima Herac, Peter Mazal, Andrea Haitel, Martin Susani, Richard Moriggl, Zoran Culig, Lukas Kenner. IL-6/Stat3 signaling is an indispensable modulator of oncogene-induced cellular senescence. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3138. doi:10.1158/1538-7445.AM2014-3138
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-3138
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    The Telomerase Reverse Transcriptase ( hTERT ) Gene Is a Direct Target of the Histone Methyltransferase SMYD3
    American Association for Cancer Research (AACR) ; 2007
    In:  Cancer Research Vol. 67, No. 6 ( 2007-03-15), p. 2626-2631
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 67, No. 6 ( 2007-03-15), p. 2626-2631
    Abstract: Recent evidence has accumulated that the dynamic histone methylation mediated by histone methyltransferases and demethylases plays key roles in regulation of chromatin structure and transcription. In the present study, we show that SET and MYND domain-containing protein 3 (SMYD3), a histone methyltransferase implicated in oncogenesis, directly trans-activates the telomerase reverse transcriptase (hTERT) gene that is essential for cellular immortalization and transformation. SMYD3 occupies its binding motifs on the hTERT promoter and is required for maintenance of histone H3-K4 trimethylation, thereby contributing to inducible and constitutive hTERT expression in normal and malignant human cells. Knocking down SMYD3 in tumor cells abolished trimethylation of H3-K4, attenuated the occupancy by the trans-activators c-MYC and Sp1, and led to diminished histone H3 acetylation in the hTERT promoter region, which was coupled with down-regulation of hTERT mRNA and telomerase activity. These results suggest that SMYD3-mediated trimethylation of H3-K4 functions as a licensing element for subsequent transcription factor binding to the hTERT promoter. The present findings provide significant insights into regulatory mechanisms of hTERT/telomerase expression; moreover, identification of the hTERT gene as a direct target of SMYD3 contributes to a better understanding of SMYD3-mediated cellular transformation. [Cancer Res 2007;67(6):2626–31]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-06-4126
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Transient Ablation of Regulatory T cells Improves Antitumor Immunity in Colitis-Associated Colon Cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 16 ( 2014-08-15), p. 4258-4269
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 16 ( 2014-08-15), p. 4258-4269
    Abstract: Regulatory T cells (Treg) are supportive to cancer development in most tissues, but their role in colitis-associated colon cancer (CAC) remains unclear. In this study, we investigated the role of CD4+Foxp3+ Treg in a mouse model of CAC and in patients with colon cancer. These Treg were increased strongly in number in a mouse model of CAC and in the peripheral blood of patients with colon cancer, exhibiting an activated phenotype as defined by elevated expression of GARP, CD103, CTLA-4, and IL10, along with an increased suppressive effect on the proliferation and Th1 cytokine expression of CD4+CD25− responder T cells ex vivo. Transient ablation of CD4+Foxp3+ Treg during tumor development in the CAC model suppressed tumor outgrowth and distribution, accompanied by an increased number of CD8+IFNγ/granzyme B-producing effector T cells. Conversely, inactivation of IL10 in Treg did not elevate the antitumor response but instead further boosted tumor development. Our results establish a tumor-promoting function for Treg during CAC formation, but they also suggest that a selective, transient ablation of Treg can evoke antitumor responses, with implications for immunotherapeutic interventions in patients with CAC. Cancer Res; 74(16); 4258–69. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-13-3065
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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