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Nat Genet. 2013 Jul;45(7):739-746. doi: 10.1038/ng.2654. Epub 2013 Jun 2.

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

Author information

1
Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
2
BCMB Program, Weill Graduate School of Medical Sciences, Cornell University, New York, New York 10021.
3
Cancer Biology and Genetics Program, Sloan-Kettering Institute, 1275 York Avenue, New York, New York 10021, USA.
4
Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
5
FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
6
Human Oncology and Pathogenesis Program, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
7
Department of Developmental Biology, Harvard School Of Dental Medicine, Boston, MA 02115, USA.
8
Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
9
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. MA.
10
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
#
Contributed equally

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.

PMID:
23727861
PMCID:
PMC4036521
DOI:
10.1038/ng.2654
[Indexed for MEDLINE]
Free PMC Article

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