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

Yu, Y.; Schleich, K.; Yue, B.; Ji, S.; Lohneis, P.; Kemper, K.; Silvis, M.S.; 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, F.A.; Zon, L.I.; Holmen, S.L.; Peeper, D.S.; Samuels, Y.; Schmitt, C.A.; Lee, S.

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

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Item Type:	Article
Title:	Targeting the senescence-overriding cooperative activity of structurally unrelated H3K9 demethylases in melanoma
Creators Name:	Yu, Y., Schleich, K., Yue, B., Ji, S., Lohneis, P., Kemper, K., Silvis, M.S., 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, F.A., Zon, L.I., Holmen, S.L., Peeper, D.S., Samuels, Y., 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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