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Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence

Nature volume 464, pages 374–379 (2010)Cite this article

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A Corrigendum to this article was published on 15 July 2010

Abstract

Cellular senescence has been recently shown to have an important role in opposing tumour initiation and promotion. Senescence induced by oncogenes or by loss of tumour suppressor genes is thought to critically depend on induction of the p19Arf–p53 pathway. The Skp2 E3-ubiquitin ligase can act as a proto-oncogene and its aberrant overexpression is frequently observed in human cancers. Here we show that although Skp2 inactivation on its own does not induce cellular senescence, aberrant proto-oncogenic signals as well as inactivation of tumour suppressor genes do trigger a potent, tumour-suppressive senescence response in mice and cells devoid of Skp2. Notably, Skp2 inactivation and oncogenic-stress-driven senescence neither elicit activation of the p19Arf–p53 pathway nor DNA damage, but instead depend on Atf4, p27 and p21. We further demonstrate that genetic Skp2 inactivation evokes cellular senescence even in oncogenic conditions in which the p19Arf–p53 response is impaired, whereas a Skp2–SCF complex inhibitor can trigger cellular senescence in p53/Pten-deficient cells and tumour regression in preclinical studies. Our findings therefore provide proof-of-principle evidence that pharmacological inhibition of Skp2 may represent a general approach for cancer prevention and therapy.

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Figure 1: Skp2 loss triggers a new senescence response in MEFs in the context of Pten inactivation and Arf deficiency by a p19 Arf –p53-independent pathway.
Figure 2: Upregulation of p27, p21 and Atf4 drives cellular senescence in Pten+/- Skp2-/- and Arf-/- Skp2-/- MEFs.
Figure 3: Skp2 deficiency restricts tumorigenesis after Pten inactivation by inducing cellular senescence in vivo.
Figure 4: Skp2 inactivation restricts tumorigenesis upon Arf deficiency.
Figure 5: Skp2 deficiency restricts prostate cancer development by triggering cellular senescence in vivo.

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Acknowledgements

We are grateful to C. J. Sherr, S. W. Lowe and M. Oren for mice and reagents. We would also like to thank B. Carver, L. DiSantis, J. Clossey and S. Megan for editing and critical reading of the manuscript, J. A. Koutcher, C. Le, C. Matei and M. Lupa for MRI analysis, as well all the members of the Pandolfi laboratory for comments and discussion. We extend our thanks to M. Rolfe, P. G. Smith, and Millennium Pharmaceuticals for discussion and for providing the MLN4924 compound. This work was supported by NIH grants to P.P.P. and M.D. Anderson Trust Scholar Award and DOD Prostate Cancer New Investigator Award to H.K.L.

Author Contributions H.K.L. and P.P.P. designed the experiments and wrote the manuscript; H.-K.L., Z.C., G.W., S.-W.L., C.N., C.-H.C., W.-L.Y., J.W. and A.E. performed the experiments; C.C.-C. and J.T-F. performed the histopathological analysis of the mice; K.I.N. provided the Skp2-/- mice.

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Author notes

  1. Zhenbang Chen & Carlos Cordon-Cardo

    Present address: Present addresses: Department of Biochemistry and Cancer Biology, Meharry Medical College, 1005 Dr D. B. Todd Jr Boulevard, Nashville, Tennessee 37208-3599, USA (Z.C.); Irving Cancer Research Center, Room 309, 1130 St. Nicholas Avenue, New York, New York 10032, USA (C.C.-C.).,

  2. Guocan Wang, Caterina Nardella and Szu-Wei Lee: These authors contribute equally to this work.

Authors and Affiliations

  1. Cancer Biology and Genetics Program,,

    Hui-Kuan Lin, Zhenbang Chen, Guocan Wang, Caterina Nardella & Pier Paolo Pandolfi

  2. Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA,

    Hui-Kuan Lin, Zhenbang Chen, Guocan Wang, Caterina Nardella, Carlos Cordon-Cardo, Julie Teruya-Feldstein & Pier Paolo Pandolfi

  3. Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA,

    Hui-Kuan Lin, Szu-Wei Lee, Chan-Hsin Chan, Wei-Lei Yang & Jing Wang

  4. Beth Israel Deaconess Cancer Center and Department of Medicine, Cancer Genetics Program, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA,

    Zhenbang Chen, Guocan Wang, Caterina Nardella, Ainara Egia & Pier Paolo Pandolfi

  5. Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan,

    Keiichi I. Nakayama

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Correspondence to Pier Paolo Pandolfi.

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Lin, HK., Chen, Z., Wang, G. et al. Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence. Nature 464, 374–379 (2010). https://doi.org/10.1038/nature08815

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