p38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis.
p38-mediated phosphorylation at T367 induces EZH2 cytoplasmic localization to promote breast cancer metastasis.
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DOI：
10.1038/s41467-018-05078-8
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发表时间：
2018-07-18
影响因子：
16.6
通讯作者：
Kleer CG
中科院分区：
文献类型：
--
作者：
Anwar T;Arellano-Garcia C;Ropa J;Chen YC;Kim HS;Yoon E;Grigsby S;Basrur V;Nesvizhskii AI;Muntean A;Gonzalez ME;Kidwell KM;Nikolovska-Coleska Z;Kleer CG
EZH 2在雌激素受体阴性（ER-）乳腺癌中的过表达促进转移。EZH 2主要被研究为多梳抑制复合物2（PRC 2）的催化组分，PRC 2通过在赖氨酸27处三甲基化组蛋白H3（H3 K27 me 3）介导基因抑制。然而，尽管在ER-乳腺癌中观察到低H3 K27 me 3水平，EZH 2如何驱动转移是未知的。在此，我们表明，在人类浸润性癌和远处转移中，在T367处磷酸化的细胞质EZH 2与ER疾病和低H3 K27 me 3水平显著相关。p38介导的EZH 2在T367处的磷酸化促进EZH 2细胞质定位并增强EZH 2与黏着斑蛋白和细胞迁移和侵袭的其他细胞骨架调节剂的结合。磷酸缺陷型T367 A-EZH 2突变体的异位表达足以抑制EZH 2细胞质表达，破坏与细胞骨架调节剂的结合，并减少EZH 2介导的粘附、迁移、侵袭和自发转移的发展。这些结果指向EZH 2促转移功能的不依赖于PRC 2的非经典机制。多梳族蛋白EZH 2在ER-乳腺癌中过表达，促进转移。在这里，作者表明，独立于polycomb组，p38在T367处对EZH 2的磷酸化促进了EZH 2的细胞质定位，与黏着斑蛋白和其他细胞迁移和侵袭调节因子结合。
Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. Here we show that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. p38-mediated EZH2 phosphorylation at T367 promotes EZH2 cytoplasmic localization and potentiates EZH2 binding to vinculin and other cytoskeletal regulators of cell migration and invasion. Ectopic expression of a phospho-deficient T367A-EZH2 mutant is sufficient to inhibit EZH2 cytoplasmic expression, disrupt binding to cytoskeletal regulators, and reduce EZH2-mediated adhesion, migration, invasion, and development of spontaneous metastasis. These results point to a PRC2-independent non-canonical mechanism of EZH2 pro-metastatic function. Polycomb group protein EZH2 is overexpressed in ER- breast cancer, promoting metastasis. Here, the authors show that independent of the polycomb group, phosphorylation of EZH2 at T367 by p38 promotes cytoplasmic localization of EZH2, binding to vinculin and other regulators of cell migration and invasion.
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影响因子：
11.2
作者：
Chen L;Mayer JA;Krisko TI;Speers CW;Wang T;Hilsenbeck SG;Brown PH
通讯作者：
Brown PH
影响因子：
6.6
作者：
Holm, Karolina;Grabau, Dorthe;Ringner, Markus
通讯作者：
Ringner, Markus
影响因子：
5.7
作者：
Burgos-Ojeda D;Wu R;McLean K;Chen YC;Talpaz M;Yoon E;Cho KR;Buckanovich RJ
通讯作者：
Buckanovich RJ
影响因子：
4.6
作者：
Bae, Woo Kyun;Yoo, Kyung Hyun;Lee, Ji Shin;Kim, Young;Chung, Ik-Joo;Park, Min Ho;Yoon, Jung Han;Furth, Priscilla A.;Hennighausen, Lothar
通讯作者：
Hennighausen, Lothar
影响因子：
1.9
作者：
Horzum, Utku;Ozdil, Berrin;Pesen-Okvur, Devrim
通讯作者：
Pesen-Okvur, Devrim