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The E3 ligase COP1 promotes ERα signaling and suppresses EMT in breast cancer

Oncogene volume 41, pages 173–190 (2022)Cite this article

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Abstract

ERα signaling drives proliferation, survival and cancer initiation in the mammary gland. Therefore, it is critical to elucidate mechanisms by which ERα expression is regulated. We show that the tumor suppressor E3 ligase COP1 promotes the degradative polyubiquitination of the microtubule-associated protein HPIP. As such, COP1 negatively regulates estrogen-dependent AKT activation in breast cancer cells. However, COP1 also induces ERα expression and ERα-dependent gene transcription, at least through c-Jun degradation. COP1 and ERα levels are positively correlated in clinical cases of breast cancer. COP1 also supports the metabolic reprogramming by estrogens, including glycolysis. On the other hand, COP1 suppresses EMT in breast cancer cells. COP1 deficiency also contributes to Tamoxifen resistance, at least through protective autophagy. Therefore, COP1 acts as an oncogenic E3 ligase by promoting ERα signaling but also acts as a tumor suppressor candidate by preventing EMT, which reflects a dual role of COP1 in breast cancer.

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Fig. 1: COP1 binds HPIP.
Fig. 2: COP1 negatively regulates estrogens-dependent TBK1 and AKT activation but promotes ERα expression.
Fig. 3: COP1 promotes ERα expression in breast cancer.
Fig. 4: The induction of ERα target genes by estrogens rely on COP1.
Fig. 5: c-Jun is a negative regulator of ERα expression.
Fig. 6: Metabolic reprogramming by estrogens requires COP1.
Fig. 7: COP1 expression prevents EMT.
Fig. 8: COP1 negatively regulates the pool of cancer stem cells.
Fig. 9: COP1 deficiency promotes Tamoxifen resistance.
Fig. 10: A dual role for COP1 expression in breast cancer.

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Acknowledgements

The authors thank Arnaud Blomme (Laboratory of Cancer Signaling, University of Liege, Liege, Belgium) for the gift of PyMT cells. The authors also thank the GIGA Imaging and Flow Cytometry Facility as well as the GIGA Genomics Platform for RNA-Sequencing analyses. This study was supported by Grants from the Belgian National Funds for Scientific Research (FNRS) and from Special Research Funds (FSR) at the University of Liege, the Belgian foundation against Cancer (FAF-F/2016/794), as well as from the Walloon Excellence in Life Sciences and Biotechnology (WELBIO-CR-2015A-02). We are also grateful to the “Fondation Leon Fredericq” of the CHU Liege for its financial support. A. Chariot and P. Close are Research Director and Senior Research Associate at the FNRS, respectively. The authors declare no conflict of interest.

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Author notes

  1. These authors contributed equally: Kateryna Shostak, Alain Chariot.

Authors and Affiliations

  1. Interdisciplinary Cluster for Applied Genoproteomics, University of Liege, CHU, Sart-Tilman, Liège, Belgium

    Seng Chuan Tang, Quentin Lion, Olivier Peulen, Philippe Chariot, Arnaud Lavergne, Alice Mayer, Paula Allepuz Fuster, Pierre Close, Kateryna Shostak & Alain Chariot

  2. Laboratory of Medical Chemistry, GIGA Stem Cells, University of Liege, CHU, Sart-Tilman, Liège, Belgium

    Seng Chuan Tang, Quentin Lion, Philippe Chariot, Paula Allepuz Fuster, Kateryna Shostak & Alain Chariot

  3. Metastasis Research Laboratory, GIGA Cancer, University of Liege, CHU, Sart-Tilman, Liège, Belgium

    Olivier Peulen

  4. GIGA Genomics Platform, University of Liege, CHU, Sart-Tilman, Liège, Belgium

    Arnaud Lavergne & Alice Mayer

  5. Laboratory of Cancer Signaling, GIGA Stem Cells, University of Liege, CHU, Sart-Tilman, 4000, Liège, Belgium

    Pierre Close

  6. Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Wavres, Belgium

    Pierre Close & Alain Chariot

  7. Institute for Pathology-University Hospital of Cologne, Cologne, Germany

    Sebastian Klein, Alexandra Florin & Reinhard Büttner

  8. Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS 3633, Paris, France

    Ivan Nemazanyy

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Contributions

Conceptualization, AC and KS; Methodology, SCT, QL, OP, PCh, AL, A M, PAF, PCl, SK, AF and IN; Investigation, SCT, QL, PCh, AL, AM, PAF, PCl, SK, AF and IN; Formal Analysis: SCT, OP, KS and AC; Writing—Original Draft, AC; Funding Acquisition, AC; Resources, RB; Supervision, AC.

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Correspondence to Alain Chariot.

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Tang, S.C., Lion, Q., Peulen, O. et al. The E3 ligase COP1 promotes ERα signaling and suppresses EMT in breast cancer. Oncogene 41, 173–190 (2022). https://doi.org/10.1038/s41388-021-02038-3

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