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Zinc finger protein 367 promotes metastasis by inhibiting the Hippo pathway in breast cancer

Oncogene volume 39, pages 2568–2582 (2020)Cite this article

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Abstract

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.

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Fig. 1: High expression of ZNF367 correlates with breast cancer metastasis and poor prognosis.
Fig. 2: ZNF367 promotes breast cancer metastasis by increasing the presence of CTCs.
Fig. 3: ZNF367 inhibits anoikis in breast cancer.
Fig. 4: ZNF367 activates YAP1 signaling.
Fig. 5: ZNF367 directly activates two negative regulators of the Hippo signaling pathway.
Fig. 6: Pharmacological targeting of YAP1 inhibits ZNF367-driven breast cancer metastasis.
Fig. 7: Clinical relevance of ZNF367 with YAP1 and CTCs in breast cancer patients.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (No. 81772800); Fundamental Research Funds for the Central Universities (No. 2017KFYXJJ258).

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Author notes

  1. These authors contributed equally: Xianqiu Wu, Xin Zhang, Liang Yu

Authors and Affiliations

  1. State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China

    Xianqiu Wu, Xin Zhang, Liping Ye, Yue Li, Xiaoqing Sun, Ying Ouyang, Xiangfu Chen, Libing Song & Xi Lin

  2. The department of gastrointestinal surgery, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China

    Xianqiu Wu

  3. Clinical Experimental Center, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, 529030, China

    Xin Zhang & Dong Ren

  4. Department of Vascular and Breast Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China

    Liang Yu

  5. Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Chen Zhang

  6. Institute of Structural & Molecular Biology, Division of Biosciences, University College London, London, WC1E 6BT, UK

    Lefan Yu

  7. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Pian Liu

  8. Ultrasonic Department, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China

    Xi Lin

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Contributions

PL and XL designed the project. XW, XZ, and LY carried out most of the experimental work. XW and XZ conducted the bioinformatic analysis, immunohistochemistry staining, and in vivo studies. CZ, LY, YL, and XS conducted western blot analysis, plasmid constructs, and immunoprecipitation. LY, YO, and XC conducted cell culture and PCR analysis. DR conducted language editing. PL and XL wrote the manuscript. LS, PL, and XL supervised the project.

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Correspondence to Pian Liu or Xi Lin.

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Wu, X., Zhang, X., Yu, L. et al. Zinc finger protein 367 promotes metastasis by inhibiting the Hippo pathway in breast cancer. Oncogene 39, 2568–2582 (2020). https://doi.org/10.1038/s41388-020-1166-y

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