Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy.
Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy.
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DOI：
10.1038/s41591-018-0034-6
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发表时间：
2018-06
期刊：
影响因子：
82.9
通讯作者：
Shilatifard A
中科院分区：
文献类型：
--
作者：
Wang L;Zhao Z;Ozark PA;Fantini D;Marshall SA;Rendleman EJ;Cozzolino KA;Louis N;He X;Morgan MA;Takahashi YH;Collings CK;Smith ER;Ntziachristos P;Savas JN;Zou L;Hashizume R;Meeks JJ;Shilatifard A
MLL 3（也称为KMT 2C）是COMPASS亚基，在基因增强子处实现H3 K4单甲基化。KMT 2C经常在一系列人类肿瘤中引起点突变，然而这些病变如何确切地改变MLL 3功能并有助于肿瘤发生尚不清楚。在这里，我们报告了MLL 3在其植物同源结构域（PHD）重复内的癌症突变热点，并证明该结构域介导与组蛋白H2 A去泛素化酶和肿瘤抑制因子BAP 1的关联。癌症相关的MLL 3 PHD突变破坏MLL 3和BAP 1之间的相互作用，并与患者生存率差相关。携带MLL 3 PHD突变或缺乏BAP 1的癌细胞表现出MLL 3和H3 K27脱甲基酶UTX（KDM 6A）的增强子募集减少。因此，抑制携带BAP 1或MLL 3突变的肿瘤细胞中多梳阻遏物复合物2（PRC 2）的H3 K27甲基转移酶活性，恢复正常的基因表达模式并损害体内细胞增殖。这项研究为MLL 3 PHD突变在癌症中的作用提供了机制见解，并指出了polycomb-COMPASS的平衡状态的恢复，用于治疗由这些表观遗传因子突变引起的癌症。
MLL3 (also named KMT2C) is a COMPASS subunit that implements H3K4 mono-methylation at gene enhancers. KMT2C frequently incurs point-mutations across a range of human tumors, nevertheless precisely how these lesions alter MLL3 function and contribute to oncogenesis is unclear. Here we report a cancer mutational hotspot in MLL3 within its Plant Homeo Domain (PHD) repeats and demonstrate that this domain mediates association with the histone H2A deubiquitinase and tumor suppressor BAP1. Cancer-associated MLL3 PHD mutations disrupt the interaction between MLL3 and BAP1 and correlate with poor patient survival. Cancer cells bearing MLL3 PHD mutations or lacking BAP1, exhibit reduced enhancer recruitment of MLL3 and the H3K27 demethylase UTX (KDM6A). As the result, inhibiting the H3K27 methyltransferase activity of polycomb repressor complex 2 (PRC2) in tumor cells harboring BAP1 or MLL3 mutations, restores normal gene expression patterns and impairs cell proliferation in vivo. This study provides mechanistic insight for the role of MLL3 PHD mutations in cancer and points to restoration of the balanced state of polycomb-COMPASS for the treatment of cancers resulting from mutations in these epigenetic factors.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
64.8
作者：
Ellis, Matthew J.;Ding, Li;Shen, Dong;Luo, Jingqin;Suman, Vera J.;Wallis, John W.;Van Tine, Brian A.;Hoog, Jeremy;Goiffon, Reece J.;Goldstein, Theodore C.;Ng, Sam;Lin, Li;Crowder, Robert;Snider, Jacqueline;Ballman, Karla;Weber, Jason;Chen, Ken;Koboldt, Daniel C.;Kandoth, Cyriac;Schierding, William S.;McMichael, Joshua F.;Miller, Christopher A.;Lu, Charles;Harris, Christopher C.;McLellan, Michael D.;Wendl, Michael C.;DeSchryver, Katherine;Allred, D. Craig;Esserman, Laura;Unzeitig, Gary;Margenthaler, Julie;Babiera, G. V.;Marcom, P. Kelly;Guenther, J. M.;Leitch, Marilyn;Hunt, Kelly;Olson, John;Tao, Yu;Maher, Christopher A.;Fulton, Lucinda L.;Fulton, Robert S.;Harrison, Michelle;Oberkfell, Ben;Du, Feiyu;Demeter, Ryan;Vickery, Tammi L.;Elhammali, Adnan;Piwnica-Worms, Helen;McDonald, Sandra;Watson, Mark;Dooling, David J.;Ota, David;Chang, Li-Wei;Bose, Ron;Ley, Timothy J.;Piwnica-Worms, David;Stuart, Joshua M.;Wilson, Richard K.;Mardis, Elaine R.
通讯作者：
Mardis, Elaine R.
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：
64.8
作者：
Ray Chaudhuri A;Callen E;Ding X;Gogola E;Duarte AA;Lee JE;Wong N;Lafarga V;Calvo JA;Panzarino NJ;John S;Day A;Crespo AV;Shen B;Starnes LM;de Ruiter JR;Daniel JA;Konstantinopoulos PA;Cortez D;Cantor SB;Fernandez-Capetillo O;Ge K;Jonkers J;Rottenberg S;Sharan SK;Nussenzweig A
通讯作者：
Nussenzweig A
影响因子：
16
作者：
Kubicek, Stefan;O'Sullivan, Roderick J.;Jenuwein, Thomas
通讯作者：
Jenuwein, Thomas