1. Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma
- Author
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Sheri L. Holmen, Steffi Treitschke, Clemens A. Schmitt, Ellen van Rooijen, Kolja Schleich, Sujuan Ji, Philipp Lohneis, Christian Speck, Soyoung Lee, Yardena Samuels, Melanie Werner-Klein, Kristel Kemper, Bin Yue, Nouar Qutob, Daniel S. Peeper, Frédérick A. Mallette, Lianjie Li, Leonard I. Zon, Abdel G. Elkahloun, Yong Yu, Svenja Meierjohann, Maurice Reimann, Dhriti Dhawan, Mark R. Silvis, Bernd Dörken, Biotechnology and Biological Sciences Research Council (BBSRC), Wellcome Trust, and Publica
- Subjects
0301 basic medicine ,Cancer Research ,Jumonji Domain-Containing Histone Demethylases ,Skin Neoplasms ,Cell ,LSD1 ,Ras/Braf ,Histones ,0302 clinical medicine ,Histone demethylation ,Promoter Regions, Genetic ,Zebrafish ,Melanoma ,Cellular Senescence ,Histone Demethylases ,histone demethylation ,targeted therapy ,animal models ,Cell biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Melanocytes ,Senescence ,patient-derived xenograft ,Mice, Nude ,Biology ,Methylation ,Article ,Histone H3 ,03 medical and health sciences ,Downregulation and upregulation ,medicine ,Gene silencing ,Animals ,Humans ,Oncology & Carcinogenesis ,neoplasms ,animal model ,Lysine ,JMJD2C ,Cell Biology ,Melanoma cancer ,biology.organism_classification ,medicine.disease ,H3K9 ,030104 developmental biology ,biology.protein ,Cancer research ,Demethylase ,1109 Neurosciences ,1112 Oncology And Carcinogenesis - 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 tri-methylated 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.
- Published
- 2015