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Slug is temporally regulated by cyclin E in cell cycle and controls genome stability

Oncogene volume 34, pages 1116–1125 (2015)Cite this article

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Abstract

The transcriptional repressor Slug is best known to control epithelial–mesenchymal transition (EMT) and promote cancer invasion/metastasis. In this study, we demonstrate that Slug is temporally regulated during cell cycle progression. At G1/S transition, cyclin E–cyclin-dependent kinase 2 mediates the phosphorylation of Slug at Ser-54 and Ser-104, resulting in its ubiquitylation and degradation. Non-phosphorylatable Slug is markedly stabilized at G1/S transition compared with wild-type Slug and greatly leads to downregulation of DNA synthesis and checkpoint-related proteins, including TOP1, DNA Ligase IV and Rad17, reduces cell proliferation, delays S-phase progression and contributes to genome instability. Our results indicate that Slug has multifaceted roles in cancer progression by controlling both EMT and genome stability.

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Acknowledgements

The proteomics data analysis by LTQ-Orbitrap XL hybrid mass spectrometer was performed by the Academia Sinica Common Mass Spectrometry Facilities located at the Institute of Biological Chemistry, Taipei, Taiwan. shRNA constructs were obtained from the National RNAi Core Facility at the Institute of Molecular Biology/Genomic Research Center, Academia Sinica, Taipei, Taiwan. We thank Szu-Hua Pan, Pei-Fang Hung and Shu-Wei Lin for technical assistance. S-PW is supported by a Human Frontier Science Program long-term fellowship. This work was supported by grants from the National Science Council (NSC99-2628-B-006-031-MY3, NSC101-2325-B-006-018, NSC100-2321-B-002-071, NSC101-2321-B-002-068 and NSC102-2811-B-002-069) and National Taiwan University (101R7601–2).

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Author notes

  1. S-P Wang

    Present address: 10Current address: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, USA.,

Authors and Affiliations

  1. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    W-L Wang, S-H Kao, S-P Wang & P-C Yang

  2. Institute of Clinical Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan

    W-L Wang & T-M Hong

  3. Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan

    H-C Huang

  4. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    S-H Kao, T-H Hsiao & P-C Yang

  5. Institute of Statistical Science, Academia Sinica, Taipei, Taiwan

    Y-C Hsu & K-C Li

  6. Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan

    Y-T Wang & Y-J Chen

  7. Institute of Chemistry, Academia Sinica, Taipei, Taiwan

    Y-T Wang & Y-J Chen

  8. Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan

    S-L Yu

  9. NTU Center of Genomic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

    P-C Yang

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Correspondence to T-M Hong.

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Wang, WL., Huang, HC., Kao, SH. et al. Slug is temporally regulated by cyclin E in cell cycle and controls genome stability. Oncogene 34, 1116–1125 (2015). https://doi.org/10.1038/onc.2014.58

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