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Cancer Cell. 2018 Feb 12;33(2):322-336.e8. doi: 10.1016/j.ccell.2018.01.002.

Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma.

Author information

1
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.
2
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Medical Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, 13353 Berlin, Germany.
3
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, 10117 Berlin, Germany.
4
Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
5
Department of Surgery, University of Utah Health Sciences Center & Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
6
Weizmann Institute of Science, Department of Molecular Cell Biology, Rehovot 7610001, Israel.
7
Howard Hughes Medical Institute, Stem Cell Program and the Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
8
Regensburg Center for Interventional Immunology (RCI) and University Medical Center of Regensburg, 93053 Regensburg, Germany; Experimental Medicine and Therapy Research, University of Regensburg, 93053 Regensburg, Germany.
9
University of Würzburg, Physiological Chemistry, Biocenter, 97074 Würzburg, Germany.
10
National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
11
Fraunhofer-Institute for Toxicology and Experimental Medicine, 93053 Regensburg, Germany.
12
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Medical Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, 13353 Berlin, Germany; Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium), Partner Site Berlin, Germany.
13
Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, and MRC London Institute of Medical Sciences (LMS), London W12 0NN, UK.
14
Department of Medicine, Université de Montréal, Maisonneuve-Rosemont Hospital Research Centre, Montréal, QC H1T 2M4, Canada.
15
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Medical Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, 13353 Berlin, Germany; Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium), Partner Site Berlin, Germany. Electronic address: clemens.schmitt@charite.de.

Abstract

Oncogene-induced senescence, e.g., in melanocytic nevi, terminates the expansion of pre-malignant cells via transcriptional silencing of proliferation-related genes due to decoration of their promoters with repressive trimethylated histone H3 lysine 9 (H3K9) marks. We show here that structurally distinct H3K9-active demethylases-the lysine-specific demethylase-1 (LSD1) and several Jumonji C domain-containing moieties (such as JMJD2C)-disable senescence and permit Ras/Braf-evoked transformation. In mouse and zebrafish models, enforced LSD1 or JMJD2C expression promoted Braf-V600E-driven melanomagenesis. A large subset of established melanoma cell lines and primary human melanoma samples presented with a collective upregulation of related and unrelated H3K9 demethylase activities, whose targeted inhibition restored senescence, even in Braf inhibitor-resistant melanomas, evoked secondary immune effects and controlled tumor growth in vivo.

KEYWORDS:

H3K9; JMJD2C; LSD1; Ras/Braf; animal models; cellular senescence; histone demethylation; melanoma; patient-derived xenograft; targeted therapy

PMID:
29438700
PMCID:
PMC5977991
DOI:
10.1016/j.ccell.2018.01.002
[Indexed for MEDLINE]
Free PMC Article

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