Zbtb7a suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion
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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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These two factors have been primarily reported to induce senescence in prostate cancer and repress senescence in mice primary tail fibroblast cells, consistent with our findings.
“While there is no previous evidence supporting the broad senescence features of these two factors, they have been primarily reported to induce senescence in prostate cancer and repress senescence in mice primary tail fibroblast cells, respectively,113,114 which is consistent with our findings.”
From Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators (2024) · cites this paper as [113]
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- Authors
- Wang, G., Lunardi, A., Zhang, J., Chen, Z., Ala, U., Webster, K. A., Tay, Y., Gonzalez-Billalabeitia, E., Egia, A., Shaffer, D. R., Carver, B., Liu, X.-S., Taulli, R., Kuo, W. P., Nardella, C., Signoretti, S., Cordon-Cardo, C., Gerald, W. L., & Pandolfi, P. P.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Pandolfi, Pier Paolo
- ORCID
- Venue
- Nature Genetics
- Published
- 2013-06-02
- Volume
- 45
- Issue
- 7
- Pages
- 739-746
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC4036521
- OpenAlex
- W2104628579
- Cited by
- 137
- References
- 75
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 9 · 2023: 11 · 2022: 12 · 2021: 5 · 2020: 10 · 2019: 17 · 2018: 11 · 2017: 12 · 2016: 12 · 2015: 15 · 2014: 11 · 2013: 7
- FWCI
- 12.22
- Type
- journal article
- Language
- en
- Update notices
- correction (2026-02-09)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Trento) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- National Cancer Institute (RC2CA147940, R01 CA102142-7, R01CA102142, P30CA008748, U54CA163069)
- National Institute on Minority Health and Health Disparities (G12MD007586)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- ZBTB7A, prostate cancer, PTEN loss, SOX9, tumor invasion, MIA, H19, long non-coding RNA, retinoblastoma protein, oncosuppression, tumor suppressor, prostate tumorigenesis
- MeSH terms
- Proto-Oncogene Mas, Animals, Cell Transformation, Neoplastic, DNA-Binding Proteins, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Neoplasm Invasiveness, Prostatic Neoplasms, Transcription Factors, Signal Transduction, Down-Regulation, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Cellular Senescence, Cell Line, Tumor, PTEN Phosphohydrolase, Mice, SOX9 Transcription Factor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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