| Literature DB >> 29438700 |
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.
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.Entities:
Keywords: H3K9; JMJD2C; LSD1; Ras/Braf; animal models; cellular senescence; histone demethylation; melanoma; patient-derived xenograft; targeted therapy
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Year: 2018 PMID： 29438700 PMCID： PMC5977991 DOI： 10.1016/j.ccell.2018.01.002
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743