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

Item Type:	Article
Title:	Targeting the senescence-overriding cooperative activity of structurally unrelated H3K9 demethylases in melanoma
Creators Name:	Yu, Y. and Schleich, K. and Yue, B. and Ji, S. and Lohneis, P. and Kemper, K. and Silvis, M.S. and Qutob, N. and van Rooijen, E. and Werner-Klein, M. and Li, L. and Dhawan, D. and Meierjohann, S. and Reimann, M. and Elkahloun, A. and Treitschke, S. and Dörken, B. and Speck, C. and Mallette, F.A. and Zon, L.I. and Holmen, S.L. and Peeper, D.S. and Samuels, Y. and Schmitt, C.A. and Lee, S.
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:	Ras/Braf, Cellular Senescence, H3K9, Histone Demethylation, JMJD2C, LSD1, Animal Models, Melanoma, Patient-Derived Xenograft, Targeted Therapy, Animals, Mice
Source:	Cancer Cell
ISSN:	1535-6108
Publisher:	Cell Press / Elsevier
Volume:	33
Number:	2
Page Range:	322-336
Date:	12 February 2018
Additional Information:	Erratum in: Cancer Cell 33(4):785.
Official Publication:	https://doi.org/10.1016/j.ccell.2018.01.002
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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