TY - JOUR
T1 - Zbtb7a suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion
AU - Wang, Guocan
AU - Lunardi, Andrea
AU - Zhang, Jiangwen
AU - Chen, Zhenbang
AU - Ala, Ugo
AU - Webster, Kaitlyn A.
AU - Tay, Yvonne
AU - Gonzalez-Billalabeitia, Enrique
AU - Egia, Ainara
AU - Shaffer, David R.
AU - Carver, Brett
AU - Liu, Xue Song
AU - Taulli, Riccardo
AU - Kuo, Winston Patrick
AU - Nardella, Caterina
AU - Signoretti, Sabina
AU - Cordon-Cardo, Carlos
AU - Gerald, William L.
AU - Pandolfi, Pier Paolo
N1 - Funding Information:
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.
PY - 2013/7
Y1 - 2013/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84879645484&partnerID=8YFLogxK
U2 - 10.1038/ng.2654
DO - 10.1038/ng.2654
M3 - Article
C2 - 23727861
AN - SCOPUS:84879645484
SN - 1061-4036
VL - 45
SP - 739
EP - 746
JO - Nature Genetics
JF - Nature Genetics
IS - 7
ER -