Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma.
Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma.
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DOI：
10.1016/j.ccell.2018.01.002
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发表时间：
2018-02-12
期刊：
影响因子：
50.3
通讯作者：
Lee S
中科院分区：
文献类型：
--
作者：
Yu Y;Schleich K;Yue B;Ji S;Lohneis P;Kemper K;Silvis MR;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
致癌基因诱导的衰老，例如，在黑素细胞痣中，通过增殖相关基因的转录沉默终止恶变前细胞的扩增，所述增殖相关基因的转录沉默是由于它们的启动子被抑制性三甲基化组蛋白H3赖氨酸9（H3 K9）标记所修饰。我们在这里表明，结构上不同的H3 K9活性脱甲基酶-赖氨酸特异性脱甲基酶-1（LSD 1）和几个Jumonji C结构域包含的部分（如JMJD 2C）-禁用衰老，并允许Ras/Braf诱发的转化。在小鼠和斑马鱼模型中，LSD 1或JMJD 2C的强制表达促进了Braf-V600 E驱动的黑色素瘤发生。建立的黑色素瘤细胞系和原代人黑色素瘤样品的一个大的子集呈现相关和不相关的H3 K9脱甲基酶活性的集体上调，其靶向抑制恢复衰老，即使在Braf荧光素耐药黑色素瘤中，诱发继发性免疫效应并控制体内肿瘤生长。Yu等人表明，两种不同类型的组蛋白H3赖氨酸9（H3 K9）脱甲基酶LSD 1和JMJD 2C通过使E2 F靶基因表达而使致癌Ras或Braf诱导的衰老失效，这允许转化。H3 K9脱甲基酶的抑制恢复衰老并控制肿瘤生长。
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 tri-methylated 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. Yu et al. show that two different types of histone H3 lysine 9 (H3K9) demethylases, LSD1 and JMJD2C, disable oncogenic Ras- or Braf-induced senescence by enabling the expression of E2F target genes, which permits transformation. Inhibition of the H3K9 demethylases restores senescence and controls tumor growth.
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影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
8.8
作者：
Kemper K;Krijgsman O;Kong X;Cornelissen-Steijger P;Shahrabi A;Weeber F;van der Velden DL;Bleijerveld OB;Kuilman T;Kluin RJC;Sun C;Voest EE;Ju YS;Schumacher TNM;Altelaar AFM;McDermott U;Adams DJ;Blank CU;Haanen JB;Peeper DS
通讯作者：
Peeper DS
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
64.8
作者：
Kang, Tae-Won;Yevsa, Tetyana;Zender, Lars
通讯作者：
Zender, Lars