4 years ago

Combined loss of EAF2 and p53 induces prostate carcinogenesis in male mice.

Rigatti, Graham, Parwani, Pilch, Jing, Zhong, Pascal, Wang, Ai, Nelson, Song
Mutations in the p53 tumor suppressor are frequent in patients with castration-resistant prostate cancer but less so in patients with localized disease, and Li-Fraumeni patients with germline p53 mutations do not have an increased incidence of prostate cancer, suggesting that additional molecular and/or genetic changes are required for p53 to promote prostate carcinogenesis. EAF2 is a tumor suppressor that is frequently down-regulated in advanced prostate cancer. Previous studies have suggested that p53 binds to EAF2, providing a potential mechanism for their functional interactions. Here we tested whether p53 and EAF2 could functionally interact in prostate cancer cells and whether concurrent inactivation of p53 and EAF2 could promote prostate carcinogenesis in a murine knockout model. Endogenous p53 co-precipitated with EAF2 in prostate cancer cells, and deletion mutagenesis indicated that this interaction was mediated through the C-terminus of EAF2 and the DNA binding domain of p53. Concurrent knockdown of p53 and EAF2 induced an increase in proliferation and migration in cultured prostate cancer cells, and conventional p53 and EAF2 knockout mice developed prostate cancer. In human prostate cancer specimens, concurrent p53 nuclear staining and EAF2 down-regulation was associated with high Gleason Score. These findings suggest that EAF2 and p53 functionally interact in prostate tumor suppression and that simultaneous inactivation of EAF2 and p53 can drive prostate carcinogenesis.

Publisher URL: http://doi.org/10.1210/en.2017-00409

DOI: 10.1210/en.2017-00409

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