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FBXL14 abolishes breast cancer progression by targeting CDCP1 for proteasomal degradation

Oncogene volume 37, pages 5794–5809 (2018)Cite this article

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Abstract

Understanding the molecular mechanisms that underlie the aggressive behavior and relapse of breast cancer may help in the development of novel therapeutic interventions. CUB-domain-containing protein 1 (CDCP1), a transmembrane adaptor protein, is highly maintained and required in the context of cellular metastatic potential in triple-negative breast cancer (TNBC). For this reason, gene expression levels of CDCP1 have been considered as a prognostic marker in TNBC. However, not rarely, transcript levels of genes do not reflect always the levels of proteins, due to the post-transcriptional regulation. Here we show that miR-17/20a control the FBXL14 E3 ligase, establishing FBXL14 as an upstream regulator of the CDCP1 pathway. FBXL14 acts as an novel interaction partner of CDCP1, and facilitates its ubiquitination and proteasomal degradation with an enhanced capacity to suppress CDCP1 protein stability that eventually prevents CDCP1 target genes involved in breast cancer metastasis. Our findings first time uncovers the regulatory mechanism of CDCP-1 protein stabilization, more predictable criteria than gene expression levels for prognosis of breast cancer patients.

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Acknowledgements

This work was supported by the National Research Foundation (NRF) and Ministry of Science, ICT and Future Planning, Korean Government, through its National Nuclear Technology Program NRF-2016R1E1A1A01942075 and NRF-2015M2A2A7A01044998.

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Author notes

  1. These authors contributed equally: Yan-Hong Cui, Hyeonmi Kim

Authors and Affiliations

  1. Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, 04763, Republic of Korea

    Yan-Hong Cui, Hyeonmi Kim, Rae-Kwon Kim, Nizam Uddin, Ki-Chun Yoo, Jae Hyeok Kang, Mi-Young Choi, Neha Kaushik & Su-Jae Lee

  2. Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, 01812, Korea

    Minyoung Lee

  3. Research Institute, Dongnam Institute of Radiological & Medical Sciences, Busan, South Korea

    Joo Mi Yi

  4. College of Pharmacy, Seoul National University, Seoul, Korea

    Hyuk-Jin Cha & Ok-Seon Kwon

  5. Division of Basic Radiation Bioscience, Korea Institute of Radiological & Medical Sciences, Seoul, Korea

    In-Hwa Bae

  6. Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

    Min-Jung Kim

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Correspondence to Neha Kaushik or Su-Jae Lee.

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Cui, YH., Kim, H., Lee, M. et al. FBXL14 abolishes breast cancer progression by targeting CDCP1 for proteasomal degradation. Oncogene 37, 5794–5809 (2018). https://doi.org/10.1038/s41388-018-0372-3

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