State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Oncogene. 2022 Jan;41(5):647-656. doi: 10.1038/s41388-021-02098-5. Epub 2021 Nov 19.
Emerging evidence shows the association between nuclear envelope and tumor progression, however, the functional contributions of specific constituents of the nuclear envelope remain largely unclear. We found that the expression level of transmembrane protein 201 (TMEM201), an integral inner nuclear membrane protein of unknown function, was significantly elevated in invasive breast cancer and predicted poor breast cancer prognosis. We showed that TMEM201, as a positive modulator, was both necessary and sufficient to regulate the migration and invasion of breast cancer cells in vitro and in vivo. Mechanistically, RNA-sequencing analysis and validation showed that TMEM201 deficiency inhibited epithelial-to-mesenchymal transition and transforming growth factor-β signaling. Finally, we showed that TMEM201 physically interacted with SMAD2/3 and was required for the phosphorylation of SMAD2/3, nuclear translocation and transcriptional activation of the TGFβ. Thus, we demonstrated that specific inner nuclear membrane component mediated signal-dependent transcriptional effects to control breast cancer metastasis.
越来越多的证据表明核膜与肿瘤进展之间存在关联，然而，核膜的特定成分的功能贡献在很大程度上仍不清楚。我们发现，跨膜蛋白 201（TMEM201）的表达水平在浸润性乳腺癌中显著升高，TMEM201 是一种功能未知的核膜内整合蛋白，其表达水平预测乳腺癌预后不良。我们表明，TMEM201 作为一个正调节剂，在体外和体内调节乳腺癌细胞的迁移和侵袭是必需且充分的。从机制上讲，RNA 测序分析和验证表明，TMEM201 缺乏抑制上皮-间充质转化和转化生长因子-β信号。最后，我们表明 TMEM201 与 SMAD2/3 物理相互作用，并且是 SMAD2/3 的磷酸化、核转位和 TGFβ 的转录激活所必需的。因此，我们证明了特定的核膜内组件介导信号依赖性转录效应，以控制乳腺癌转移。
