FBXL10 contributes to the development of diffuse large B-cell lymphoma by epigenetically enhancing ERK1/2 signaling pathway.
FBXL10 contributes to the development of diffuse large B-cell lymphoma by epigenetically enhancing ERK1/2 signaling pathway.
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FBXL10 通过表观遗传增强 ERK1/2 信号通路促进弥漫性大 B 细胞淋巴瘤的发展
DOI：
10.1038/s41419-017-0066-8
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发表时间：
2018-01-19
影响因子：
9
通讯作者：
Wu X
中科院分区：
文献类型：
--
作者：
Zhao X;Wang X;Li Q;Chen W;Zhang N;Kong Y;Lv J;Cao L;Lin D;Wang X;Xu G;Wu X
表观遗传修饰剂已经成为控制不同癌症生物学的关键因素。在本文中，我们发现FBXL 10（也称为KDM 2B或JHDM 1B），Polycomb抑制复合物的重要成员，在人弥漫性大B细胞淋巴瘤（DLBCL）组织和衍生细胞系中过表达。在DLBCL细胞中通过特异性短发夹RNA敲低FBXL 10抑制细胞增殖并诱导凋亡。此外，DLBCL细胞中的FBXL 10耗尽消除了小鼠异种移植模型中的肿瘤生长。通过RNA测序分析，我们发现FBXL 10缺失后去阻遏的关键基因之一是DUSP 6，它编码ERK 1/2的磷酸酶。FBXL 10通过募集Polycomb组蛋白和在DUSP 6启动子处沉积抑制性组蛋白修饰来维持DUSP 6表达的沉默。因此，FBXL 10是DLBCL细胞中ERK 1/2磷酸化所必需的。此外，我们表明，ERK 1/2激活和FBXL 10耗尽细胞的增殖率可以通过下调DUSP 6表达来挽救。这些发现表明FBXL 10可能是DLBCL的一个有前途的治疗靶点，并建立了表观遗传调节因子与激酶信号通路的联系。
Epigenetic modifiers have emerged as critical factors governing the biology of different cancers. Herein we show that FBXL10 (also called KDM2B or JHDM1B), an important member of Polycomb repressive complexes, is overexpressed in human diffuse large B-cell lymphoma (DLBCL) tissues and the derived cell lines. Knocking down FBXL10 by specific short hairpin RNAs in DLBCL cells inhibits cell proliferation and induces apoptosisin vitro. Moreover, FBXL10 depletion in DLBCL cells abrogates tumor growth in mouse xenograft models. Through the analysis of RNA sequencing, we find that one of the key derepressed genes by depletion of FBXL10 isDUSP6, encoding a phosphatase for ERK1/2. Mechanistically FBXL10 maintains the silencing ofDUSP6expression via recruitment of Polycomb group proteins and deposition of repressive histone modifications at theDUSP6promoter. Consistently, FBXL10 is required for ERK1/2 phosphorylation in DLBCL cells. Furthermore, we show that ERK1/2 activation and the proliferation rate of FBXL10-depleted cells can be rescued by downregulation of DUSP6 expression. These findings indicate that FBXL10 may be a promising therapeutic target in DLBCL and establish a link of epigenetic regulators to kinase signaling pathways.
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影响因子：
7.7
作者：
Farcas AM;Blackledge NP;Sudbery I;Long HK;McGouran JF;Rose NR;Lee S;Sims D;Cerase A;Sheahan TW;Koseki H;Brockdorff N;Ponting CP;Kessler BM;Klose RJ
通讯作者：
Klose RJ
影响因子：
11.2
作者：
Dai B;Zhao XF;Hagner P;Shapiro P;Mazan-Mamczarz K;Zhao S;Natkunam Y;Gartenhaus RB
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Gartenhaus RB
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20.3
作者：
Bhalla, Savita;Evens, Andrew M.;Gartenhaus, Ronald B.
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Gartenhaus, Ronald B.
影响因子：
64.8
作者：
Alizadeh, AA;Eisen, MB;Staudt, LM
通讯作者：
Staudt, LM
影响因子：
48
作者：
Kim D;Langmead B;Salzberg SL
通讯作者：
Salzberg SL