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

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Title: Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma.
Authors: Yu, Y
Schleich, K
Yue, B
Ji, S
Lohneis, P
Kemper, K
Silvis, MS
Qutob, N
Van Rooijen, E
Werner-Klein, M
Li, L
Dhawan, D
Meierjohann, S
Reimann, M
Elkahloun, A
Treitschke, S
Dörken, B
Speck, C
Mallette, FA
Zon, LI
Holmen, SL
Peeper, DS
Samuels, Y
Schmitt, CA
Lee, S
Item Type: Journal Article
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.
Issue Date: 12-Feb-2018
Date of Acceptance: 4-Jan-2018
URI: http://hdl.handle.net/10044/1/57079
DOI: https://dx.doi.org/10.1016/j.ccell.2018.01.002
ISSN: 1535-6108
Publisher: Elsevier (Cell Press)
Start Page: 322
End Page: 336.e8
Journal / Book Title: Cancer Cell
Volume: 33
Issue: 2
Copyright Statement: © 2018, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor/Funder: Biotechnology and Biological Sciences Research Council (BBSRC)
Wellcome Trust
Biotechnology and Biological Sciences Research Council (BBSRC)
Funder's Grant Number: BB/M003760/1
107903/Z/15/Z
BB/N000323/1
Keywords: H3K9
JMJD2C
LSD1
Ras/Braf
animal models
cellular senescence
histone demethylation
melanoma
patient-derived xenograft
targeted therapy
1112 Oncology And Carcinogenesis
1109 Neurosciences
Oncology & Carcinogenesis
Publication Status: Published
Appears in Collections:Clinical Sciences
Molecular Sciences
Faculty of Medicine



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