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

Yong Yu; Kolja Schleich; Bin Yue; Sujuan Ji; Philipp Lohneis; Kristel Kemper; Mark R Silvis; Nouar Qutob; Ellen van Rooijen; Melanie Werner-Klein; Lianjie Li; Dhriti Dhawan; Svenja Meierjohann; Maurice Reimann; Abdel Elkahloun; Steffi Treitschke; Bernd Dörken; Christian Speck; Frédérick A Mallette; Leonard I Zon; Sheri L Holmen; Daniel S Peeper; Yardena Samuels; Clemens A Schmitt; Soyoung Lee

doi:10.1016/j.ccell.2018.01.002

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

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

Authors

Yong Yu¹, Kolja Schleich², Bin Yue², Sujuan Ji², Philipp Lohneis³, Kristel Kemper⁴, Mark R Silvis⁵, Nouar Qutob⁶, Ellen van Rooijen⁷, Melanie Werner-Klein⁸, Lianjie Li², Dhriti Dhawan², Svenja Meierjohann⁹, Maurice Reimann², Abdel Elkahloun¹⁰, Steffi Treitschke¹¹, Bernd Dörken¹², Christian Speck¹³, Frédérick A Mallette¹⁴, Leonard I Zon⁷, Sheri L Holmen⁵, Daniel S Peeper⁴, Yardena Samuels⁶, Clemens A Schmitt¹⁵, Soyoung Lee¹²

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Histone Demethylases / genetics*
Histones / metabolism
Humans
Jumonji Domain-Containing Histone Demethylases / genetics*
Lysine / genetics
Lysine / metabolism
Melanoma / genetics*
Methylation
Mice, Nude
Promoter Regions, Genetic / genetics

Substances

Histones
KDM4C protein, human
Histone Demethylases
Jmjd2c protein, mouse
Jumonji Domain-Containing Histone Demethylases
KDM1a protein, mouse
KDM1A protein, human
Lysine

Abstract

Publication types

MeSH terms

Substances

Grants and funding