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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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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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.
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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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DOI: https://doi.org/10.1038/ng.2654
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