Hong Zhe, Xu Chengdang, Zheng Shengfeng, Wang Xinan, Tao Yiran, Tan Yao, Lin Guowen, Wu Denglong, Ye Dingwei
Department of Urology, Fudan University Shanghai Cancer Center, 200032, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China.
Cell Death Discov. 2023 Oct 24;9(1):392. doi: 10.1038/s41420-023-01682-w.
Nucleophosmin 1 (NPM1) is a multifunctional protein that promotes tumor progression in various cancers and is associated with a poor prognosis of prostate cancer (PCa). However, the mechanism by which NPM1 exerts its malignant potential in PCa remains elusive. Here, we showed that NPM1 is overexpressed in PCa cell lines and tissues and that the dysregulation of NPM1 promotes PCa proliferation. We also demonstrated that NPM1 transcriptionally upregulates c-Myc expression in PCa cells that is diminished by blockade of bromodomain-containing protein 4 (BRD4). Furthermore, we detected a correlation between NPM1 and c-Myc in patient PCa specimens. Mechanistically, NPM1 influences and cooperates with BRD4 to facilitate c-Myc transcription to promote PCa progression. In addition, JQ1, a bromodomain and extra-terminal domain (BET) inhibitor, in combination with NPM1 inhibition suppresses PCa progression in vitro and in vivo. These results indicate that NPM1 promotes PCa progression through a c-Myc -mediated pathway via BRD4, and blockade of the NPM1-c-Myc oncogenic pathway may be a therapeutic strategy for PCa.
核磷蛋白1（NPM1）是一种多功能蛋白，可促进多种癌症的肿瘤进展，并与前列腺癌（PCa）的不良预后相关。然而，NPM1在PCa中发挥其恶性潜能的机制仍不清楚。在此，我们表明NPM1在PCa细胞系和组织中过表达，且NPM1的失调促进PCa增殖。我们还证明，NPM1在PCa细胞中转录上调c-Myc的表达，而这种上调可被含溴结构域蛋白4（BRD4）的阻断所减弱。此外，我们在患者PCa标本中检测到NPM1与c-Myc之间存在相关性。从机制上讲，NPM1影响并与BRD4协同作用，以促进c-Myc转录，从而推动PCa进展。此外，JQ1，一种含溴结构域和额外末端结构域（BET）抑制剂，与NPM1抑制联合使用可在体外和体内抑制PCa进展。这些结果表明，NPM1通过BRD4经由c-Myc介导的途径促进PCa进展，阻断NPM1-c-Myc致癌途径可能是PCa的一种治疗策略。
