Wang Yao, Pascal Laura E, Zhong Mingming, Ai Junkui, Wang Dan, Jing Yifeng, Pilch Jan, Song Qiong, Rigatti Lora H, Graham Lara E, Nelson Joel B, Parwani Anil V, Wang Zhou
Department of Urology, China-Japan Union Hospital of Jilin University, China.
Department of Urology, University of Pittsburgh School of Medicine.
Endocrinology. 2017 Dec 1;158(12):4189-4205. doi: 10.1210/en.2017-00409.
Mutations in the p53 tumor suppressor are frequent in patients with castration-resistant prostate cancer but less so in patients with localized disease, and patients who have Li-Fraumeni 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. ELL-associated factor 2 (EAF2) is a tumor suppressor that is frequently downregulated in advanced prostate cancer. Previous studies have suggested that p53 binds to EAF2, providing a potential mechanism for their functional interactions. In this study, 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 coprecipitated 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 downregulation 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.
在去势抵抗性前列腺癌患者中，p53肿瘤抑制基因的突变很常见，但在局限性疾病患者中则较少见，并且患有李-弗劳梅尼综合征且携带种系p53突变的患者前列腺癌发病率并未增加，这表明p53促进前列腺癌发生还需要其他分子和/或基因改变。ELL相关因子2（EAF2）是一种肿瘤抑制因子，在晚期前列腺癌中经常下调。先前的研究表明p53与EAF2结合，为它们的功能相互作用提供了一种潜在机制。在本研究中，我们测试了p53和EAF2在前列腺癌细胞中是否能发生功能相互作用，以及p53和EAF2的同时失活是否能在小鼠基因敲除模型中促进前列腺癌发生。内源性p53在前列腺癌细胞中与EAF2共沉淀，缺失诱变表明这种相互作用是通过EAF2的C末端和p53的DNA结合结构域介导的。同时敲低p53和EAF2可导致培养的前列腺癌细胞增殖和迁移增加，常规p53和EAF2基因敲除小鼠会发生前列腺癌。在人类前列腺癌标本中，p53核染色和EAF2下调同时出现与高Gleason评分相关。这些发现表明EAF2和p53在前列腺肿瘤抑制中存在功能相互作用，并且EAF2和p53的同时失活可驱动前列腺癌发生。
