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Targeting the senescence-overriding cooperative activity of structurally unrelated H3K9 demethylases in melanoma

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


Cancer cell 33 (2018), No.2, pp.322-336.e8
ISSN: 1878-3686
ISSN: 1535-6108
Journal Article
Fraunhofer ITEM ()
cellular senescence; H3K9; Histone demethylation; JMJD2C; LSD1; animal model; melanoma; patient-derived xenograft; targeted therapy

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.