Lrf suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion
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Author
Wang, Guocan
Zhang, Jiangwen
Chen, Zhenbang
Ala, Ugo
Webster, Kaitlyn A.
Tay, Yvonne
Gonzalez-Billalabeitia, Enrique
Egia, Ainara
Shaffer, David R.
Carver, Brett
Liu, Xue-Song
Taulli, Riccardo
Kuo, Winston Patrick
Nardella, Caterina
Cordon-Cardo, Carlos
Gerald, William L.
Pandolfi, Pier Paolo
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/ng.2654Metadata
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Wang, G., A. Lunardi, J. Zhang, Z. Chen, U. Ala, K. A. Webster, Y. Tay, et al. 2013. “Lrf suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion.” Nature genetics 45 (7): 739-746. doi:10.1038/ng.2654. http://dx.doi.org/10.1038/ng.2654.Abstract
Lrf has been previously described as a powerful proto-oncogene. Here we surprisingly demonstrate that Lrf plays a critical oncosuppressive role in the prostate. Prostate specific inactivation of Lrf leads to a dramatic acceleration of Pten-loss-driven prostate tumorigenesis through a bypass of Pten-loss-induced senescence (PICS). We show that LRF physically interacts with and functionally antagonizes SOX9 transcriptional activity on key target genes such as MIA, which is involved in tumor cell invasion, and H19, a long non-coding RNA precursor for an Rb-targeting miRNA. Inactivation of Lrf in vivo leads to Rb down-regulation, PICS bypass and invasive prostate cancer. Importantly, we found that LRF is genetically lost, as well as down-regulated at both the mRNA and protein levels in a subset of human advanced prostate cancers. Thus, we identify LRF as a context-dependent cancer gene that can act as an oncogene in some contexts but also displays oncosuppressive-like activity in Pten−/− tumors.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036521/pdf/Terms of Use
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