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Hui-Kuan Lin1,2,3, Zhenbang Chen1,2,4,6, Guocan Wang1,2,4,7, Caterina Nardella1,2,4,7, Szu-Wei Lee3,7, Chan-Hsin Chan3, Wei-Lei Yang3, Jing Wang3, Ainara Egia4, Keiichi I. Nakayama5, Carlos Cordon-Cardo2,6, Julie Teruya-Feldstein2 & Pier Paolo Pandolfi1,2,4
1 Cancer Biology and Genetics Program,
2 Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
3 Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
4 Cancer Genetics Program, Beth Israel Deaconess Cancer Center and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA
5 Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan
6 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.).
7 These authors contribute equally to this work.
Correspondence to: Pier Paolo Pandolfi1,2,4 Correspondence and requests for materials should be addressed to P.P.P. (Email:).
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.
