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

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.

• Authors: Guocan Wang, Andrea Lunardi, Jiangwen Zhang, Zhenbang Chen, Ugo Ala, Kaitlyn A Webster, Yvonne Tay, Enrique Gonzalez-Billalabeitia, Ainara Egia, David R Shaffer, Brett Carver, Xue-Song Liu, Riccardo Taulli, Winston Patrick Kuo, Caterina Nardella, Sabina Signoretti, Carlos Cordon-Cardo, William L Gerald, Pier Paolo Pandolfi
• Journal: Nature genetics (Nat Genet) Vol. 45 Issue 7 Pg. 739-746 (Jul 2013) ISSN: 1546-1718 [Electronic] United States
• PMID: 23727861 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• MAS1 protein, human
• Proto-Oncogene Mas
• SOX9 Transcription Factor
• SOX9 protein, human
• Transcription Factors
• ZBTB7A protein, human
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Animals
• Cell Line, Tumor
• Cell Transformation, Neoplastic (genetics)
• Cellular Senescence (genetics)
• DNA-Binding Proteins (genetics, metabolism, physiology)
• Down-Regulation (genetics)
• Female
• Gene Expression Regulation, Neoplastic (physiology)
• Genes, Tumor Suppressor (physiology)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Models, Biological
• Neoplasm Invasiveness
• PTEN Phosphohydrolase (genetics, metabolism)
• Prostatic Neoplasms (genetics, pathology)
• Proto-Oncogene Mas
• SOX9 Transcription Factor (genetics, metabolism, physiology)
• Signal Transduction (genetics)
• Transcription Factors (genetics, metabolism, physiology)