Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Shanghai Putuo People's Hospital, School of Medicine, Tongji University, Shanghai 200060, China; Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China; Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
Dev Cell. 2019 Feb 11;48(3):345-360.e7. doi: 10.1016/j.devcel.2018.11.033. Epub 2018 Dec 27.
NANOG is an essential transcriptional factor for the maintenance of embryonic stem cells (ESCs) and cancer stem cells (CSCs) in prostate cancer (PCa). However, the regulation mechanism of NANOG protein stability in cancer progression is still elusive. Here, we report that NANOG is degraded by SPOP, a frequently mutated tumor suppressor of PCa. Cancer-associated mutations of SPOP or the mutation of NANOG at S68Y abrogates the SPOP-mediated NANOG degradation, leading to elevated PCa cancer stemness and poor prognosis. In addition, SPOP-mediated NANOG degradation is controlled by the AMPK-BRAF signal axis through the phosphorylation of NANOG at Ser68, which blocked the interaction between SPOP and NANOG. Thus, our study provides a regulation mechanism of PCa stemness controlled by phosphorylation-mediated NANOG stability, which helps to identify novel drug targets and improve therapeutic strategy for PCa.
NANOG 是维持胚胎干细胞（ESCs）和前列腺癌（PCa）中的癌症干细胞（CSCs）的必需转录因子。然而，NANOG 蛋白稳定性在癌症进展中的调节机制仍不清楚。在这里，我们报告 NANOG 被 SPOP 降解，SPOP 是 PCa 的一种频繁突变的肿瘤抑制因子。SPOP 的癌症相关突变或 NANOG 的 S68Y 突变会破坏 SPOP 介导的 NANOG 降解，导致 PCa 癌症干性增加和预后不良。此外，AMPK-BRAF 信号轴通过 NANOG 丝氨酸 68 位的磷酸化控制 SPOP 介导的 NANOG 降解，从而阻止 SPOP 和 NANOG 之间的相互作用。因此，我们的研究提供了一个由磷酸化介导的 NANOG 稳定性控制的 PCa 干性调节机制，这有助于确定新的药物靶点并改善 PCa 的治疗策略。
