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Zbtb7a suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion

Nature Genetics volume 45, pages 739–746 (2013)Cite this article

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Abstract

Zbtb7a has previously been described as a powerful proto-oncogene. Here we unexpectedly demonstrate that Zbtb7a has a critical oncosuppressive role in the prostate. Prostate-specific inactivation of Zbtb7a leads to a marked acceleration of Pten loss–driven prostate tumorigenesis through bypass of Pten loss–induced cellular senescence (PICS). We show that ZBTB7A physically interacts with SOX9 and functionally antagonizes its transcriptional activity on key target genes such as MIA, which is involved in tumor cell invasion, and H19, a long noncoding RNA precursor for an RB-targeting microRNA. Inactivation of Zbtb7a in vivo leads to Rb downregulation, PICS bypass and invasive prostate cancer. Notably, we found that ZBTB7A is genetically lost, as well as downregulated at both the mRNA and protein levels, in a subset of human advanced prostate cancers. Thus, we identify ZBTB7A as a context-dependent cancer gene that can act as an oncogene in some contexts but also has oncosuppressive-like activity in PTEN-null tumors.

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Figure 1: Conditional deletion of Zbtb7a in mouse prostate strongly promotes Pten loss–induced prostate tumorigenesis.
Figure 2: Loss of Zbtb7a leads to senescence bypass and increased proliferation.
Figure 3: Hyperactivation of Sox9 in Pten and Zbtb7a double-null prostate tumors downregulates Rb expression through H19 and miR-675.
Figure 4: ZBTB7A downregulation in human prostate cancers correlates with tumor progression and metastasis.

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References

  1. Maeda, T. et al. Role of the proto-oncogene Pokemon in cellular transformation and ARF repression. Nature 433, 278–285 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Pendergrast, P.S., Wang, C., Hernandez, N. & Huang, S. FBI-1 can stimulate HIV-1 Tat activity and is targeted to a novel subnuclear domain that includes the Tat-P–TEFb–containing nuclear speckles. Mol. Biol. Cell 13, 915–929 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kukita, A. et al. Osteoclast-derived zinc finger (OCZF) protein with POZ domain, a possible transcriptional repressor, is involved in osteoclastogenesis. Blood 94, 1987–1997 (1999).

    CAS  PubMed  Google Scholar 

  4. Davies, J.M. et al. Novel BTB/POZ domain zinc-finger protein, LRF, is a potential target of the LAZ-3/BCL-6 oncogene. Oncogene 18, 365–375 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Chen, X., Whitney, E.M., Gao, S.Y. & Yang, V.W. Transcriptional profiling of Kruppel-like factor 4 reveals a function in cell cycle regulation and epithelial differentiation. J. Mol. Biol. 326, 665–677 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Costoya, J.A. et al. Essential role of Plzf in maintenance of spermatogonial stem cells. Nat. Genet. 36, 653–659 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. He, X. et al. The zinc finger transcription factor Th-POK regulates CD4 versus CD8 T-cell lineage commitment. Nature 433, 826–833 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Pasqualucci, L. et al. Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma. Blood 101, 2914–2923 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Sun, G. et al. The zinc finger protein cKrox directs CD4 lineage differentiation during intrathymic T cell positive selection. Nat. Immunol. 6, 373–381 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Jiang, L. et al. Overexpression of proto-oncogene FBI-1 activates membrane type 1–matrix metalloproteinase in association with adverse outcome in ovarian cancers. Mol. Cancer 9, 318 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Aggarwal, A. et al. Expression of leukemia/lymphoma-related factor (LRF/POKEMON) in human breast carcinoma and other cancers. Exp. Mol. Pathol. 89, 140–148 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Qu, H. et al. ZBTB7 overexpression contributes to malignancy in breast cancer. Cancer Invest. 28, 672–678 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Vredeveld, L.C., Rowland, B.D., Douma, S., Bernards, R. & Peeper, D.S. Functional identification of LRF as an oncogene that bypasses RASV12-induced senescence via upregulation of CYCLIN E. Carcinogenesis 31, 201–207 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Zhao, Z.H. et al. Overexpression of Pokemon in non–small cell lung cancer and foreshowing tumor biological behavior as well as clinical results. Lung Cancer 62, 113–119 (2008).

    Article  PubMed  Google Scholar 

  15. Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wu, X. et al. Generation of a prostate epithelial cell–specific Cre transgenic mouse model for tissue-specific gene ablation. Mech. Dev. 101, 61–69 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Trotman, L.C. et al. Pten dose dictates cancer progression in the prostate. PLoS Biol. 1, E59 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Alimonti, A. et al. Subtle variations in Pten dose determine cancer susceptibility. Nat. Genet. 42, 454–458 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ding, Z. et al. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature 470, 269–273 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Majumder, P.K. et al. A prostatic intraepithelial neoplasia–dependent p27Kip1 checkpoint induces senescence and inhibits cell proliferation and cancer progression. Cancer Cell 14, 146–155 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen, Z. et al. Differential p53-independent outcomes of p19Arf loss in oncogenesis. Sci. Signal. 2, ra44 (2009).

    PubMed  PubMed Central  Google Scholar 

  22. Zhang, Z., Rosen, D.G., Yao, J.L., Huang, J. & Liu, J. Expression of p14ARF, p15INK4b, p16INK4a, and DCR2 increases during prostate cancer progression. Mod. Pathol. 19, 1339–1343 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Xie, W.F., Zhang, X., Sakano, S., Lefebvre, V. & Sandell, L.J. Trans-activation of the mouse cartilage-derived retinoic acid–sensitive protein gene by Sox9. J. Bone Miner. Res. 14, 757–763 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Wang, D.H. et al. Aberrant epithelial-mesenchymal Hedgehog signaling characterizes Barrett's metaplasia. Gastroenterology 138, 1810–1822 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Dudek, K.A., Lafont, J.E., Martinez-Sanchez, A. & Murphy, C.L. Type II collagen expression is regulated by tissue-specific miR-675 in human articular chondrocytes. J. Biol. Chem. 285, 24381–24387 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ho Sui, S.J., Fulton, D.L., Arenillas, D.J., Kwon, A.T. & Wasserman, W.W. oPOSSUM: integrated tools for analysis of regulatory motif over-representation. Nucleic Acids Res. 35, W245–W252 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ho Sui, S.J. et al. oPOSSUM: identification of over-represented transcription factor binding sites in co-expressed genes. Nucleic Acids Res. 33, 3154–3164 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kwon, A.T., Arenillas, D.J., Worsley Hunt, R. & Wasserman, W.W. oPOSSUM-3: advanced analysis of regulatory motif over-representation across genes or ChIP-Seq datasets. G3 (Bethesda) 2, 987–1002 (2012).

    Article  CAS  Google Scholar 

  29. Mootha, V.K. et al. PGC-1α–responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Thomsen, M.K. et al. SOX9 elevation in the prostate promotes proliferation and cooperates with PTEN loss to drive tumor formation. Cancer Res. 70, 979–987 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang, H. et al. SOX9 is expressed in human fetal prostate epithelium and enhances prostate cancer invasion. Cancer Res. 68, 1625–1630 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Murakami, S., Kan, M., McKeehan, W.L. & de Crombrugghe, B. Up-regulation of the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway. Proc. Natl. Acad. Sci. USA 97, 1113–1118 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Müller, H. et al. Deleted in malignant brain tumors 1 is present in the vascular extracellular matrix and promotes angiogenesis. Arterioscler. Thromb. Vasc. Biol. 32, 442–448 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Robbe, C. et al. DMBT1 expression and glycosylation during the adenoma-carcinoma sequence in colorectal cancer. Biochem. Soc. Trans. 33, 730–732 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Kang, W. et al. Induction of DMBT1 expression by reduced ERK activity during a gastric mucosa differentiation–like process and its association with human gastric cancer. Carcinogenesis 26, 1129–1137 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Cheung, W. et al. Application of a global proteomic approach to archival precursor lesions: deleted in malignant brain tumors 1 and tissue transglutaminase 2 are upregulated in pancreatic cancer precursors. Pancreatology 8, 608–616 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tynan, S. et al. The putative tumor suppressor deleted in malignant brain tumors 1 is an estrogen-regulated gene in rodent and primate endometrial epithelium. Endocrinology 146, 1066–1073 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Kang, W. & Reid, K.B. DMBT1, a regulator of mucosal homeostasis through the linking of mucosal defense and regeneration? FEBS Lett. 540, 21–25 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Schmidt, J. & Bosserhoff, A.K. Processing of MIA protein during melanoma cell migration. Int. J. Cancer 125, 1587–1594 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Bosserhoff, A.K., Echtenacher, B., Hein, R. & Buettner, R. Functional role of melanoma inhibitory activity in regulating invasion and metastasis of malignant melanoma cells in vivo. Melanoma Res. 11, 417–421 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Bosserhoff, A.K. et al. Active detachment involves inhibition of cell-matrix contacts of malignant melanoma cells by secretion of melanoma inhibitory activity. Lab. Invest. 83, 1583–1594 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Guba, M. et al. Overexpression of melanoma inhibitory activity (MIA) enhances extravasation and metastasis of A-mel 3 melanoma cells in vivo. Br. J. Cancer 83, 1216–1222 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Stahlecker, J. et al. MIA as a reliable tumor marker in the serum of patients with malignant melanoma. Anticancer Res. 20, 5041–5044 (2000).

    CAS  PubMed  Google Scholar 

  45. Cai, X. & Cullen, B.R. The imprinted H19 noncoding RNA is a primary microRNA precursor. RNA 13, 313–316 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tsang, W.P. et al. Oncofetal H19-derived miR-675 regulates tumor suppressor RB in human colorectal cancer. Carcinogenesis 31, 350–358 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Chicas, A. et al. Dissecting the unique role of the retinoblastoma tumor suppressor during cellular senescence. Cancer Cell 17, 376–387 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sun, H. et al. E2f binding–deficient Rb1 protein suppresses prostate tumor progression in vivo. Proc. Natl. Acad. Sci. USA 108, 704–709 (2011).

    Article  PubMed  Google Scholar 

  49. Lunardi, A. et al. A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation therapy resistance in prostate cancer. Nat. Genet. published online; doi:10.1038/ng.2650 (2 June 2013).

  50. Luo, J.H. et al. Gene expression analysis of prostate cancers. Mol. Carcinog. 33, 25–35 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Liu, P. et al. Sex-determining region Y box 4 is a transforming oncogene in human prostate cancer cells. Cancer Res. 66, 4011–4019 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. LaTulippe, E. et al. Comprehensive gene expression analysis of prostate cancer reveals distinct transcriptional programs associated with metastatic disease. Cancer Res. 62, 4499–4506 (2002).

    CAS  PubMed  Google Scholar 

  53. Taylor, B.S. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Grasso, C.S. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239–243 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Stephenson, A.J. et al. Integration of gene expression profiling and clinical variables to predict prostate carcinoma recurrence after radical prostatectomy. Cancer 104, 290–298 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Lapointe, J. et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc. Natl. Acad. Sci. USA 101, 811–816 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Vanaja, D.K., Cheville, J.C., Iturria, S.J. & Young, C.Y. Transcriptional silencing of zinc finger protein 185 identified by expression profiling is associated with prostate cancer progression. Cancer Res. 63, 3877–3882 (2003).

    CAS  PubMed  Google Scholar 

  58. Arredouani, M.S. et al. Identification of the transcription factor single-minded homologue 2 as a potential biomarker and immunotherapy target in prostate cancer. Clin. Cancer Res. 15, 5794–5802 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Tomlins, S.A. et al. Integrative molecular concept modeling of prostate cancer progression. Nat. Genet. 39, 41–51 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Wallace, T.A. et al. Tumor immunobiological differences in prostate cancer between African-American and European-American men. Cancer Res. 68, 927–936 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Poliseno, L. et al. The proto-oncogene LRF is under post-transcriptional control of MiR-20a: implications for senescence. PLoS ONE 3, e2542 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Poliseno, L. et al. Identification of the miR-106b∼25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation. Sci. Signal. 3, ra29 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ren, B. et al. MCM7 amplification and overexpression are associated with prostate cancer progression. Oncogene 25, 1090–1098 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Sterner, J.M., Dew-Knight, S., Musahl, C., Kornbluth, S. & Horowitz, J.M. Negative regulation of DNA replication by the retinoblastoma protein is mediated by its association with MCM7. Mol. Cell Biol. 18, 2748–2757 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Tomlins, S.A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Clark, J.P. & Cooper, C.S. ETS gene fusions in prostate cancer. Nat. Rev. Urol. 6, 429–439 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Tomlins, S.A. et al. ETS gene fusions in prostate cancer: from discovery to daily clinical practice. Eur. Urol. 56, 275–286 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Navone, N.M. et al. p53 mutations in prostate cancer bone metastases suggest that selected p53 mutants in the primary site define foci with metastatic potential. J. Urol. 161, 304–308 (1999).

    Article  CAS  PubMed  Google Scholar 

  69. Qian, J. et al. Loss of p53 and c-myc overrepresentation in stage T2–3N1–3M0 prostate cancer are potential markers for cancer progression. Mod. Pathol. 15, 35–44 (2002).

    Article  PubMed  Google Scholar 

  70. Carver, B.S. et al. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat. Genet. 41, 619–624 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. King, J.C. et al. Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis. Nat. Genet. 41, 524–526 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. De Santa Barbara, P. et al. Direct interaction of SRY-related protein SOX9 and steroidogenic factor 1 regulates transcription of the human anti-Mullerian hormone gene. Mol. Cell Biol. 18, 6653–6665 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Root, D.E., Hacohen, N., Hahn, W.C., Lander, E.S. & Sabatini, D.M. Genome-scale loss-of-function screening with a lentiviral RNAi library. Nat. Methods 3, 715–719 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Maeda, T. et al. LRF is an essential downstream target of GATA1 in erythroid development and regulates BIM-dependent apoptosis. Dev. Cell 17, 527–540 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Drabkin, H.A. et al. Quantitative HOX expression in chromosomally defined subsets of acute myelogenous leukemia. Leukemia 16, 186–195 (2002).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to P. Berta (Institut de Genetique Humaine), B. de Crombrugghe (University of Texas MD Anderson Cancer Center) and A. Ullrich (Max Planck Institute) for reagents. We would also like to thank R. Hobbs, M. Dalynicolosi and T. Garvey for editing and critical reading of the manuscript, as well as X. Yuan and all members of the Pandolfi laboratory for insightful comments and discussion. A.L. has been supported in part by a fellowship from the Istituto Toscano Tumori (ITT, Italy). R.T. has been granted leave of absence from the Department of Oncology, Università degli Studi di Torino (Italy). This work has been supported by a Mouse Models of Human Cancer Consortium (MMHCC) National Cancer Institute (NCI) grant (RC2 CA147940-01) and a US National Institutes of Health (NIH) grant (R01 CA102142-7) to P.P.P.

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Author notes

  1. Zhenbang Chen, David R Shaffer & Carlos Cordon-Cardo

    Present address: Present addresses: Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, Tennessee, USA (Z.C.), Albany Medical Center, Albany, New York, USA (D.R.S.) and Department of Genetics and Genomic Sciences, The Mount Sinai School of Medicine, New York, New York, USA (C.C.-C.).,

  2. Guocan Wang and Andrea Lunardi: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA

    Guocan Wang, Andrea Lunardi, Ugo Ala, Kaitlyn A Webster, Yvonne Tay, Enrique Gonzalez-Billalabeitia, Ainara Egia, Xue-Song Liu, Riccardo Taulli, Caterina Nardella & Pier Paolo Pandolfi

  2. Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Guocan Wang, Andrea Lunardi, Ugo Ala, Kaitlyn A Webster, Yvonne Tay, Enrique Gonzalez-Billalabeitia, Ainara Egia, Xue-Song Liu, Riccardo Taulli, Caterina Nardella & Pier Paolo Pandolfi

  3. Biochemistry, Cell & Molecular Biology Program, Weill Graduate School of Medical Sciences, Cornell University, New York, New York, USA

    Guocan Wang

  4. Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Guocan Wang, Zhenbang Chen, David R Shaffer, Caterina Nardella & Pier Paolo Pandolfi

  5. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Guocan Wang, Zhenbang Chen, David R Shaffer, Caterina Nardella, Carlos Cordon-Cardo, William L Gerald & Pier Paolo Pandolfi

  6. Faculty of Arts and Sciences Center for Systems Biology, Harvard University, Cambridge, Massachusetts, USA

    Jiangwen Zhang

  7. Department of Surgery, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Brett Carver

  8. Department of Developmental Biology, Harvard School Of Dental Medicine, Boston, Massachusetts, USA

    Winston Patrick Kuo

  9. Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Caterina Nardella

  10. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Sabina Signoretti

  11. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Sabina Signoretti

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Contributions

G.W., A.L. and P.P.P. designed, realized and analyzed the experiments. W.L.G., B.C., U.A. and J.Z. conducted the human genetic analysis. K.A.W. and A.E. performed the immunohistochemistry on mouse prostate samples. R.T., W.P.K., Z.C., D.R.S., Y.T., E.G.-B., X.-S.L. and C.N. helped with the experiments. C.C.-C. and S.S. reviewed all mouse pathology. G.W., A.L. and P.P.P. wrote the manuscript.

Corresponding author

Correspondence to Pier Paolo Pandolfi.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7, Supplementary Tables 2–8 (PDF 5369 kb)

Supplementary Table 1

Differentially expressed genes in Pten-Lrf double null versus Pten null mouse prostate. (XLSX 571 kb)

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Wang, G., Lunardi, A., Zhang, J. et al. Zbtb7a suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion. Nat Genet 45, 739–746 (2013). https://doi.org/10.1038/ng.2654

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