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α-Parvin promotes breast cancer progression and metastasis through interaction with G3BP2 and regulation of TWIST1 signaling

Oncogene volume 38, pages 4856–4874 (2019)Cite this article

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Abstract

Identification of molecular alterations driving breast cancer progression is critical for the development of effective therapy. In this study, we show that the level of α-parvin is elevated in triple-negative breast cancer cells. The depletion of α-parvin from triple-negative breast cancer cells effectively inhibits breast cancer cell growth, migration, and invasion in vitro, and tumor progression and metastasis in vivo. At the molecular level, we identify Ras-GTPase-activing protein SH3-domain-binding protein 2 (G3BP2) as an α-parvin-binding protein. Knockdown of α-parvin promotes G3BP2 interaction with TWIST1, increases ubiquitination and proteasome-dependent degradation of TWIST1, and consequently reduces the cellular level of TWIST1 and its downstream signaling. Importantly, the depletion of G3BP2 reverses the reduction in the level and signaling of TWIST1 and the suppression of breast cancer progression induced by the loss of α-parvin. Furthermore, the re-expression of an α-parvin mutant in which the G3BP2-binding site is ablated, unlike that of wild-type α-parvin, in α-parvin-deficient breast cancer cells, is unable to restore the level and signaling of TWIST1 and promote breast cancer progression. Finally, we show that protein level of α-parvin is highly positively correlated with that of TWIST1 in human triple-negative breast cancer patients. Our studies reveal a novel signaling pathway consisting of α-parvin, G3BP2, and TWIST1 that regulates breast cancer progression and metastasis, and suggest that the activation of this signaling pathway is a key factor for driving the progression and poor clinical outcome of human ER-negative breast cancer.

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Acknowledgements

We thank Dr. Ruijun Tian of the Department of Chemistry, Southern University of Science and Technology, for help with nano LC-MS/MS analyses, Dr. Z-M Yuan (Harvard School of Public Health) for the Flag-G3BP2a construct, and Drs. Jason D. Weber (Washington University) and Yandong Zhang (Southern University of Science and Technology) for pLVX-AcGFP1-N1 and pLVX-IRES-Hyg vectors. This work was supported by the Chinese Ministry of Science and Technology (2016YFC1302100), the National Natural Science Foundation of China (81772983, 81430068, and 31471311), the Natural Science Foundation of Guangdong Province (2017B030301018), and the Shenzhen Innovation Committee of Science and Technology, China (JCYJ20170817104854302, ZDSYS20140509142721429, and JCYJ20150831142427959).

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  1. These authors contributed equally: Ying Sun, Yanyan Ding, Chen Guo

Authors and Affiliations

  1. Department of Biology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, and Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, 518055, China

    Ying Sun, Yanyan Ding, Chen Guo, Chengmin Liu, Ping Ma, Shuang Ma, Zhe Wang, Jie Liu, Tao Qian, Luyao Ma & Yi Deng

  2. Department of Pathology, School of Medicine and University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15260, USA

    Chuanyue Wu

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Contributions

YS and CW designed the study, supervised the project, and wrote the manuscript; YD, CG, CL, PM, SM, ZW, JL, TQ, and LM performed the experiments and data analysis; YD advised on some of the experiments.

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Correspondence to Ying Sun or Chuanyue Wu.

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Sun, Y., Ding, Y., Guo, C. et al. α-Parvin promotes breast cancer progression and metastasis through interaction with G3BP2 and regulation of TWIST1 signaling. Oncogene 38, 4856–4874 (2019). https://doi.org/10.1038/s41388-019-0762-1

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