靶向黑色素瘤中结构不相关的 H3K9 去甲基酶的衰老超越协同活性。
Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma.
机构信息
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany.
Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Medical Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, 13353 Berlin, Germany.
出版信息
Cancer Cell. 2018 Feb 12;33(2):322-336.e8. doi: 10.1016/j.ccell.2018.01.002.
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.
癌基因诱导的衰老，例如在黑色素痣中，通过转录沉默与增殖相关的基因来终止恶性前细胞的扩张，因为它们的启动子被抑制性三甲基化组蛋白 H3 赖氨酸 9（H3K9）标记所修饰。我们在这里表明，结构不同的 H3K9 活性去甲基酶 - 赖氨酸特异性去甲基酶 1（LSD1）和几个包含 Jumonji C 结构域的部分（如 JMJD2C）会使衰老失活，并允许 Ras/Braf 引发的转化。在小鼠和斑马鱼模型中，强制表达 LSD1 或 JMJD2C 会促进 Braf-V600E 驱动的黑色素瘤发生。一大批已建立的黑素瘤细胞系和原发性人黑素瘤样本表现出相关和不相关的 H3K9 去甲基酶活性的集体上调，其靶向抑制作用恢复了衰老，甚至在 Braf 抑制剂耐药性黑素瘤中也是如此，引发了继发性免疫效应，并控制了体内肿瘤的生长。
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