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PINCH-1 interacts with myoferlin to promote breast cancer progression and metastasis

Oncogene volume 39, pages 2069–2087 (2020)Cite this article

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Abstract

PINCH-1 is a cytoplasmic component of the cell-extracellular matrix (ECM) adhesion machine that is frequently overexpressed in cancer. The functions and mechanism of PINCH-1 in cancer, however, remain to be determined. Here, we show that PINCH-1 interacts with myoferlin, a transmembrane protein that is critical for cancer progression. High expression of both PINCH-1 and myoferlin correlates with poor clinical outcome in human breast cancer patients. Ablation of PINCH-1 from breast cancer cells diminished myoferlin level and suppressed breast cancer cell proliferation, migration, and endothelial cell tube formation in vitro and breast tumor growth, angiogenesis and metastasis in vivo. Mechanistically, PINCH-1 controls myoferlin level through its interaction with myoferlin and regulation of its ubiquitination and proteasome-dependent degradation. Functionally, re-expression of PINCH-1, but not that of a myoferlin-binding defectiveΔLIM2 mutant, effectively reversed the inhibition of myoferlin expression and breast cancer progression induced by loss of PINCH-1. Finally, restoration of myoferlin expression was sufficient to reverse PINCH-1-deficiency induced inhibition on breast cancer progression. These results reveal a PINCH-1-myoferlin signaling axis that is critical for breast cancer progression and suggest a new strategy for therapeutic control of breast cancer.

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Fig. 1: Identification of myoferlin as a PINCH-1 binding protein.
Fig. 2: PINCH-1 ablation increases the proteasomal degradation of myoferlin.
Fig. 3: PINCH-1 ablation inhibits breast cancer cell proliferation and migration and VEGF levels.
Fig. 4: Myoferlin binding is crucial for PINCH-1-mediated regulation of cell proliferation, migration, and VEGF level.
Fig. 5: PINCH-1 regulates breast cancer cell proliferation, migration, and VEGF level through the control of myoferlin levels.
Fig. 6: Correlation of PINCH-1 and myoferlin levels in breast tumor.
Fig. 7: Loss of PINCH-1 inhibits breast cancer progression in vivo.
Fig. 8: Loss of PINCH-1 inhibits breast cancer metastasis in vivo.

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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 analysis; Dr. Jiahuai Han (Xiamen University, China) for the myoferlin cDNA; Drs. Jason D. Weber (Washington University) and Yandong Zhang (Southern University of Science and Technology) for the 3Ă— Flag tagged pLVX-IRES-Hyg vector; Dr. Andrew Hutchins (Southern University of Science and Technology) for comments on the manuscript. This work was supported by the National Natural Science Foundation of China (81772983, 81430068, and 31471311), the Chinese Ministry of Science and Technology (2016YFC1302100), the Natural Science Foundation of Guangdong Province (1914050005629 and 2017B030301018), the Shenzhen Innovation Committee of Science and Technology, China (JCYJ20170817104854302, ZDSYS20140509142721429, and JCYJ20150831142427959).

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  1. These authors contributed equally: Tao Qian, Chengmin Liu

Authors and Affiliations

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

    Tao Qian, Chengmin Liu, Yanyan Ding, Chen Guo, Renwei Cai, Xiaoxia Wang, Rong Wang, Kuo Zhang, Li Zhou, Yi Deng & Ying Sun

  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; TQ, CL, YD, CG, RC, XW, RW, KZ, and LZ performed the experiments and data analysis; YD advised on some of experiments.

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Qian, T., Liu, C., Ding, Y. et al. PINCH-1 interacts with myoferlin to promote breast cancer progression and metastasis. Oncogene 39, 2069–2087 (2020). https://doi.org/10.1038/s41388-019-1135-5

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