Zinc finger protein 367 promotes metastasis by inhibiting the Hippo pathway in breast cancer
Zinc finger protein 367 promotes metastasis by inhibiting the Hippo pathway in breast cancer
复制标题
锌指蛋白367通过抑制Hippo通路促进乳腺癌转移
DOI：
10.1038/s41388-020-1166-y
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发表时间：
2020-01-27
期刊：
影响因子：
8
通讯作者：
Lin, Xi
中科院分区：
文献类型：
--
作者：
Wu, Xianqiu;Zhang, Xin;Lin, Xi
循环肿瘤细胞(CTC)的扩散是远处转移的重要原因。然而，乳腺癌中CTCs数量增加的机制尚不清楚。在本研究中，锌指蛋白367(ZNF367)被确认为乳腺癌综合数据库中潜在的转移相关基因。ZNF367在乳腺癌组织和细胞系中表达上调，并与患者较差的无转移和总生存期显著相关。ZNF367促进肿瘤转移，并伴有CTC数量增加。在机制上，ZNF367与染色质重塑蛋白BRG1相互作用，在转录水平激活CIT和TP53BP2，导致HIPPO途径的抑制和YAP1的激活，从而引起对失巢凋亡的抵抗，增加血液循环中的CTCs。更重要的是，给予YAP1抑制剂维替普芬可使过表达ZNF367的乳腺癌细胞对失巢凋亡和无转移再敏感。我们的发现说明了ZNF367在乳腺癌中作为一个预后生物标志物的重要性，并为ZNF367过表达的转移性乳腺癌的治疗提供了一种潜在的治疗策略。
Circulating tumor cells (CTC) disseminating is an important cause of distant metastasis. However, the mechanism involved in increasing the numbers of CTCs in breast cancer is unclear. Herein, Zinc finger protein 367 (ZNF367) was identified as a potential prometastatic gene in an integrative breast cancer datasets. ZNF367 was upregulated in breast cancer tissues and cell lines, and significantly correlated with poorer metastasis-free and overall survivals in patients. ZNF367 promoted tumor metastasis accompanied with increase of CTC numbers. Mechanistically, ZNF367 interacted with chromatin remodeling protein BRG1 and transcriptionally activated CIT and TP53BP2, leading to the inhibition of the Hippo pathway and activation of YAP1, which gave rise to the resistance of anoikis and increased CTCs in the blood circulation. More importantly, administration of a YAP1 inhibitor Verteporfin resensitized ZNF367-overexpressing breast cancer cells to anoikis and abrogated metastasis. Our findings addressed the importance of ZNF367 in breast cancer as a prognostic biomarker and offered a potential therapeutic strategy for the treatment of a subset of metastatic breast cancer with ZNF367 overexpression.