IKBKE phosphorylates and stabilizes Snail to promote breast cancer invasion and metastasis
IKBKE phosphorylates and stabilizes Snail to promote breast cancer invasion and metastasis
复制标题
IKBKE磷酸化并稳定Snail促进乳腺癌侵袭和转移
DOI：
10.1038/s41418-022-00940-1
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Jianping Guo
中科院分区：
文献类型：
--
作者：
Wei Xie;Qiwei Jiang;Xueji Wu;Lei Wang;Bing Gao;Zicheng Sun;Xiaomei Zhang;Lang Bu;Ying Lin;Qiang Huang;Jie Li;Jianping Guo
IKBKE是一种非典型炎症激酶，经常被扩增或激活，在人类癌症，特别是乳腺癌中起主要的致癌作用。然而，IKBKE促进乳腺癌转移的潜在功能和潜在机制在很大程度上仍不清楚。在这里，我们报道了fikbkemp的缺失显著降低了多瘤病毒中T抗原（PyVMT）诱导的小鼠乳腺肿瘤发生和随后的肺转移。生物学上，IKBKE的异位表达加速，而IKBKE的缺失则减弱乳腺癌在体外的侵袭和迁移以及体内的肿瘤转移。在机制上，IKBKE在不同层次上严密控制转录因子Snail的稳定性，特别是通过直接磷酸化Snail，显著阻断E3连接酶β- trcp1介导的Snail降解，导致乳腺癌上皮-间质转化（EMT）和转移。这些发现共同揭示了IKBKE通过控制蜗牛丰度促进乳腺癌转移的一种新的致癌功能，并强调了以IKBKE为转移性乳腺癌治疗的潜力。
IKBKE, a non-canonical inflammatory kinase, is frequently amplified or activated, and plays predominantly oncogenic roles in human cancers, especially in breast cancer. However, the potential function and underlying mechanism of IKBKE contributing to breast cancer metastasis remain largely elusive. Here, we report that depletion ofIkbkemarkedly decreases polyoma virus middle T antigen (PyVMT)-induced mouse mammary tumorigenesis and subsequent lung metastasis. Biologically, ectopic expression of IKBKE accelerates, whereas depletion ofIKBKEattenuates breast cancer invasiveness and migration in vitro and tumor metastasis in vivo. Mechanistically, IKBKE tightly controls the stability of transcriptional factor Snail in different layers, in particular by directly phosphorylating Snail, which markedly blocks the E3 ligase β-TRCP1-mediated Snail degradation, resulting in breast cancer epithelial-mesenchymal transition (EMT) and metastasis. These findings together reveal a novel oncogenic function of IKBKE in promoting breast cancer metastasis by governing Snail abundance, and highlight the potential of targeting IKBKE for metastatic breast cancer therapies.
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影响因子：
14.9
作者：
Moreno R;Sobotzik JM;Schultz C;Schmitz ML
通讯作者：
Schmitz ML
影响因子：
56.9
作者：
tenOever, Benjamin R.;ng, Sze-Li Ng;Maniatis, Tom
通讯作者：
Maniatis, Tom
DOI：
10.1016/b978-0-12-374279-7.17002-x
发表时间：
2016
期刊：
--
影响因子：
--
作者：
Sushil Kumar;Christopher J. Chan;L. Coussens
通讯作者：
Sushil Kumar;Christopher J. Chan;L. Coussens
影响因子：
6
作者：
Guo, Jian-Ping;Shu, Shao-Kun;Cheng, Jin Q.
通讯作者：
Cheng, Jin Q.
影响因子：
15.9
作者：
Barbie, Thanh U.;Alexe, Gabriela;Gillanders, William E.
通讯作者：
Gillanders, William E.