The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma.
The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma.
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DOI：
10.1016/j.ccell.2018.01.018
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发表时间：
2018-03-12
期刊：
影响因子：
50.3
通讯作者：
Lowe SW
中科院分区：
文献类型：
--
作者：
Banito A;Li X;Laporte AN;Roe JS;Sanchez-Vega F;Huang CH;Dancsok AR;Hatzi K;Chen CC;Tschaharganeh DF;Chandwani R;Tasdemir N;Jones KB;Capecchi MR;Vakoc CR;Schultz N;Ladanyi M;Nielsen TO;Lowe SW
滑膜肉瘤是一种侵袭性癌症，总是与染色体易位有关，涉及编码SWI-SNF复合物组分SS 18和SSX（SSX 1或SSX 2）转录抑制因子的基因。使用功能基因组学，我们确定KDM 2B-组蛋白去甲基化酶和非典型的Polycomb抑制复合物1（PRC1.1）的组成部分-作为维持滑膜肉瘤细胞转化所需的选择性。SS 18-SSX 1与PRC1.1物理相互作用，并与未甲基化CpG岛上的SWI/SNF和KDM 2B复合物共缔合。通过KDM 2B，SS 18-SSX 1结合并异常激活发育调节基因的表达，否则靶向多梳介导的抑制，其在KDM 2B耗尽后恢复，导致不可逆的间充质分化。因此，SS 18-SSX 1通过劫持转录抑制复合物异常激活基因表达来解除发育程序以驱动转化。Banito等人表明滑膜肉瘤的特征性SS 18-SSX融合与KDM 2B（一种非典型的多梳抑制复合物1）相关，以异常激活发育调节的转录因子的表达，所述转录因子通常是多梳介导的基因抑制的靶。
Synovial sarcoma is an aggressive cancer invariably associated with a chromosomal translocation involving genes encoding the SWI-SNF complex component SS18 and a SSX (SSX1 or SSX2) transcriptional repressor. Using functional genomics, we identify KDM2B – a histone demethylase and component of a non-canonical Polycomb Repressive Complex 1 (PRC1.1) – as selectively required for sustaining synovial sarcoma cell transformation. SS18-SSX1 physically interacts with PRC1.1 and co-associates with SWI/SNF and KDM2B complexes on unmethylated CpG islands. Via KDM2B, SS18-SSX1 binds and aberrantly activates expression of developmentally regulated genes otherwise targets of polycomb-mediated repression, which is restored upon KDM2B depletion leading to irreversible mesenchymal differentiation. Thus, SS18-SSX1 de-regulates developmental programs to drive transformation by hijacking a transcriptional repressive complex to aberrantly activate gene expression. Banito et al. show that SS18-SSX fusions characteristic of synovial sarcoma associate with KDM2B, a non-canonical polycomb repressive complex 1, to aberrantly activate the expression of developmentally regulated transcription factors that are normally targets of polycomb mediated gene repression.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
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：
46.9
作者：
Heck, Dirk;Kowalczyk, Monika S.;Yudovich, David;Belizaire, Roger;Puram, Rishi V.;McConkey, Marie E.;Thielke, Anne;Aster, Jon C.;Regev, Aviv;Ebert, Benjamin L.
通讯作者：
Ebert, Benjamin L.
影响因子：
11.2
作者：
Baird, K;Davis, S;Meltzer, PS
通讯作者：
Meltzer, PS
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK