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Inner nuclear membrane protein TMEM201 promotes breast cancer metastasis by positive regulating TGFβ signaling

Oncogene volume 41, pages 647–656 (2022)Cite this article

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Abstract

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.

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Fig. 1: TMEM201 is increased in triple-negative breast cancers (TNBC).
Fig. 2: Loss of TMEM201 inhibits cell migration and invasion but does not affect cell proliferation.
Fig. 3: TMEM201 promotes cell migration and invasion but does not affect cell proliferation.
Fig. 4: TMEM201 promotes breast cancer lung metastasis.
Fig. 5: Loss of TMEM201 inhibits EMT and TGFβ signaling.
Fig. 6: Deficiency of TMEM201 leads to a decrease in phosphorylation of SMAD2/3.

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Acknowledgements

This work is supported by the National Natural Science Foundation of China (Grant 31871414, 81971265), Science and Technology Commission of Shanghai Municipality (19JC1416300), Shanghai Institute of Materia Medica (SIMM2004KF-01), Shanghai Municipal Human Resources and Social Security Bureau (Y91204R).

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Authors and Affiliations

  1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Ya Kong, Yutian Zhang, Hanlin Wang, Weijuan Kan, Haoran Guo, Yi Zang & Jia Li

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Ya Kong, Yutian Zhang, Haoran Guo, Yi Zang & Jia Li

  3. Department of Pharmacology, Fudan University, Shanghai, 201203, China

    Hanlin Wang

  4. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, #24 Tong Jia Xiang Street, Nanjing, 210009, China

    Yun Liu

  5. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, China

    Yi Zang & Jia Li

  6. Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, 266237, China

    Jia Li

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  1. Ya Kong
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Contributions

YK designed and performed most experiments and data analysis. YTZ helped with the knockout cell line construction and relevant analysis. HLW helped with the TCGA and other databases analysis and RNA sequencing analysis. WJK contributed to the in vivo mouse model construction. HRG assisted the immunoblots. YL helped with the plasmids construction and lentivirus package. JL and YZ participated in experimental design, data interpretation and supervised the project. YK wrote the article. All authors contributed to the final editing and approval of the paper.

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Correspondence to Yi Zang or Jia Li.

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Kong, Y., Zhang, Y., Wang, H. et al. Inner nuclear membrane protein TMEM201 promotes breast cancer metastasis by positive regulating TGFβ signaling. Oncogene 41, 647–656 (2022). https://doi.org/10.1038/s41388-021-02098-5

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