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p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug

Nature Cell Biology volume 11, pages 694–704 (2009)Cite this article

An Erratum to this article was published on 01 July 2009

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Abstract

The tumour suppressor p53 is known to prevent cancer progression by inhibiting proliferation and inducing apoptosis of tumour cells. Slug, an invasion promoter, exerts its effects by repressing E-cadherin transcription. Here we show that wild-type p53 (wtp53) suppresses cancer invasion by inducing Slug degradation, whereas mutant p53 may stabilize Slug protein. In non-small-cell lung cancer (NSCLC), mutation of p53 correlates with low MDM2, high Slug and low E-cadherin expression. This expression profile is associated with poor overall survival and short metastasis-free survival in patients with NSCLC. wtp53 upregulates MDM2 and forms a wtp53–MDM2–Slug complex that facilitates MDM2-mediated Slug degradation. Downregulation of Slug by wtp53 or MDM2 enhances E-cadherin expression and represses cancer cell invasiveness. In contrast, mutant p53 inactivates Slug degradation and leads to Slug accumulation and increased cancer cell invasiveness. Our findings indicate that wtp53 and p53 mutants may differentially control cancer invasion and metastasis through the p53–MDM2–Slug pathway.

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Figure 1: p53 mutation is associated with poor clinical outcome in patients with NSCLC, and p53 can regulate Slug protein expression.
Figure 2: Slug is unstable in p53+/+ cells and is regulated by the 26S proteasome.
Figure 3: MDM2 ubiquitin E3-ligase is involved in p53-induced Slug degradation.
Figure 4: The p53–MDM2–Slug complex facilitates Slug degradation.
Figure 5: Domain mapping of the p53–MDM2–Slug complex.
Figure 6: The effects of wtp53 and mutant p53 on Slug-mediated cancer cell invasion.
Figure 7: The signature of p53 mutation (p53mt), low MDM2 (M), high Slug (S) and low E-cadherin (E) expression is correlated with poor overall survival and early metastasis in patients with NSCLC.

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  • 19 May 2009

    In the version of this article initially published, The Myc-Ub label in Figure 3c was incorret. Arrowheads were missing in fig. 5d and 5e. A (+) sign was misplaced from the curve in Fig. 7e. These errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank H. K. Sytwu (Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan) for providing the plasmids for the lentivirus infection system, Pei-Fang Hung and Lu-Kai Wang for technical assistance, and Pei-Ying Lin for English language editing. This work was supported by the National Science Council and Department of Health, Executive Yuan of the Republic of China, through the National Research Program for Genomic Medicine Grants (DOH94-TD-G-111-020, DOH95-TD-G-111-010, DOH96-TD-G-111-009, DOH97-TD-G-111-018, DOH98-TD-G-111-007, NSC97-3112-B-002-033 and NSC97-2314-B-002-146-MY3). shRNA constructs were obtained from the National RNAi Core Facility at the Institute of Molecular Biology/Genomic Research Center, Academia Sinica, Taipei, Taiwan.

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Author notes

  1. Tse-Ming Hong and Pan-Chyr Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, 11490, Taiwan

    Shu-Ping Wang, Wen-Lung Wang & Yu-Chih Chao

  2. Department of Pathology and Graduate Institute of Pathology, National Taiwan University, Taipei, 10043, Taiwan

    Yih-Leong Chang & Chen-Tu Wu

  3. Graduate Institute of Molecular Biology, College of Medicine, National Taiwan University, Taipei, 10043, Taiwan

    Shih-Han Kao

  4. Department of Internal Medicine, National Taiwan University Hospital, Taipei, 10043, Taiwan

    Ang Yuan & Pan-Chyr Yang

  5. Department of Pathology, National Taiwan University Hospital, Taipei, 10043, Taiwan

    Chung-Wu Lin

  6. Institute of Biomedical Sciences, Academia Sinica, Taipei, 11529, Taiwan

    Shuenn-Chen Yang & Pan-Chyr Yang

  7. Department of Medical Research, National Taiwan University Hospital, Taipei, 10043, Taiwan

    Wing-Kai Chan

  8. Institute of Statistical Science, Academia Sinica, Taipei, 11529, Taiwan

    Ker-Chau Li

  9. Institute of Clinical Medicine, National Cheng Kung University, Tainan, 70101, Taiwan

    Tse-Ming Hong

  10. NTU Center for Genomic Medicine, College of Medicine, National Taiwan University, Taipei, 10043, Taiwan

    Pan-Chyr Yang

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Contributions

T.-M.H. and P.-C.Y. directed the project and contributed equally to this work. S.-P.W. performed and analysed most of the experiments. W.-L.W., Y.-C.C., S.-H.K., S.-C.Y. and W.-K.C. provided reagents and materials, and performed data analysis. Y.-L.C., C.-T.W., A.Y., C.-W.L and K.-C.L. collected and analysed samples from lung cancer patients.

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Correspondence to Pan-Chyr Yang.

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Wang, SP., Wang, WL., Chang, YL. et al. p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nat Cell Biol 11, 694–704 (2009). https://doi.org/10.1038/ncb1875

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