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Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma.
Cancer Cell ( IF 50.3 ) Pub Date : 2018-02-12 , DOI: 10.1016/j.ccell.2018.01.002
Yong Yu 1 , Kolja Schleich 2 , Bin Yue 2 , Sujuan Ji 2 , Philipp Lohneis 3 , Kristel Kemper 4 , Mark R Silvis 5 , Nouar Qutob 6 , Ellen van Rooijen 7 , Melanie Werner-Klein 8 , Lianjie Li 2 , Dhriti Dhawan 2 , Svenja Meierjohann 9 , Maurice Reimann 2 , Abdel Elkahloun 10 , Steffi Treitschke 11 , Bernd Dörken 12 , Christian Speck 13 , Frédérick A Mallette 14 , Leonard I Zon 7 , Sheri L Holmen 5 , Daniel S Peeper 4 , Yardena Samuels 6 , Clemens A Schmitt 12 , Soyoung Lee 12
Affiliation  

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.

中文翻译:

针对黑色素瘤中结构无关的 H3K9 去甲基化酶的衰老覆盖协同活动。

致癌基因诱导的衰老,例如,在黑素细胞痣中,由于增殖相关基因的启动子被抑制性三甲基化组蛋白 H3 赖氨酸 9 (H3K9) 标记修饰,因此通过转录沉默终止恶变前细胞的扩张。我们在这里展示了结构不同的 H3K9 活性去甲基化酶 - 赖氨酸特异性去甲基化酶 - 1 (LSD1) 和几个包含 Jumonji C 结构域的部分(如 JMJD2C) - 禁用衰老并允许 Ras/Braf 诱发的转化。在小鼠和斑马鱼模型中,强制性 LSD1 或 JMJD2C 表达促进了 Braf-V600E 驱动的黑素瘤形成。大量已建立的黑色素瘤细胞系和原代人黑色素瘤样本呈现出相关和不相关的 H3K9 去甲基化酶活性的集体上调,其靶向抑制恢复了衰老,
更新日期:2018-02-13
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