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E3 ubiquitin ligase CHIP attenuates cellular proliferation and invasion abilities in triple-negative breast cancer cells

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Abstract

Carboxyl terminus of Hsc-70-interacting protein (CHIP), as U-box-type ubiquitin ligase, connects the chaperone and proteasome systems and plays a pivotal role in maintaining protein homeostasis in the cytoplasm. CHIP induces the ubiquitination and degradation of diverse oncogenic substrate proteins and therefore involves in the progression of tumorigenesis. In this study, the CHIP expression was examined in different human breast cancer cell lines and a group of breast cancer tissues. We found, for the first time, that CHIP expression was correlated with the molecular subtyping of breast cancer. CHIP was least expressed in the base-like subtype of breast cancer, which are triple-negative breast cancer (TNBC) breast cancer predominantly. Accordingly, CHIP expression was evidently decreased in the TNBC MDA-MB-231 breast cancer cell line. Enforced induction of CHIP in the MDA-MB-231 cells exerted no obvious influences on cellular growth and cell cycle. The apoptotic and proliferation cells in hCHIP cells were both reduced compared to the ctrl cells. The mRNA and protein expressions of the anti-apoptotic Bcl-2 and Bcl-xL were markedly increased in the hCHIP cells compared to that of the ctrl cells. The expression of RelA was significantly reduced in the nuclear extract in hCHIP cells compared to that in the ctrl cells. The protein expressions of IKKβ were markedly decreased in the hCHIP cells compared to the ctrl cells. The reduced cellular proliferation was largely due to the attenuated IKKβ-p65/NF-κB activity. Meanwhile, the invasion ability but not the migration ability was diminished when CHIP was overexpressed in the MDA-MB-231 cells. The activity of MMP2 but not MMP9 was significantly decreased in the hCHIP cells compared to the ctrl cells. Taken together, these observations here provide functional evidence for CHIP behaved as a tumor suppressor in the TNBC breast cancer cells. CHIP influenced diverse biological aspects of the MDA-MB-231 breast cancer cells. Importantly, CHIP expression is a useful indicator of the molecular subtyping of breast cancer.

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Acknowledgements

This study was funded by grants from Suzhou Natural Science Foundation (Grant Number SS201875), Special Technical Project of Diagnosis and Treatment of Key Clinical Diseases of Suzhou (Grant Number LCZX201813), the National Natural Science Foundation of China (Grant Number 81400154), the Project of invigorating Health Care through Science, Technology and Education, Jiangsu Provincial Medical Youth Talent (Grant Number QNRC2016725), and Guiding Projects of Suzhou Science and Technology Plan (Grant Number SYSD2016112).

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  1. Jingjing Xu and Huan Wang have contribution equally to this work.

Authors and Affiliations

  1. Center for Clinical Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China

    Jingjing Xu

  2. Department of Oncology, Suining People’s Hospital, Suining, 221200, China

    Huan Wang

  3. Department of Oncology, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, 215001, China

    Wenjing Li, Kaili Liu, Tingli Zhang, Zhijie He & Feng Guo

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Contributions

FG and ZJH designed the research. JJX and HW performed the research and analyzed the data. WJL, KLL and TLZ collected the samples and performed the research. FG and JJX wrote the paper. All authors have read and approved the final version of this manuscript.

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Correspondence to Zhijie He or Feng Guo.

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All procedures performed in studies involving human participants were in accordance with the Ethics Committee of Nanjing Medical University Affiliated Suzhou Hospital.

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Xu, J., Wang, H., Li, W. et al. E3 ubiquitin ligase CHIP attenuates cellular proliferation and invasion abilities in triple-negative breast cancer cells. Clin Exp Med 20, 109–119 (2020). https://doi.org/10.1007/s10238-019-00594-3

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