SPOP suppresses pancreatic cancer progression by promoting the degradation of NANOG
SPOP suppresses pancreatic cancer progression by promoting the degradation of NANOG
复制标题
SPOP 通过促进 NANOG 降解来抑制胰腺癌进展
DOI：
10.1038/s41419-019-2017-z
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发表时间：
2019-10-17
影响因子：
9
通讯作者：
Yao, Lei
中科院分区：
文献类型：
--
作者：
Tan, Peng;Xu, Yunke;Yao, Lei
斑点型POZ结构域蛋白（SPOP）是E3泛素连接酶复合物中的一个适配器，通过泛素-蛋白酶体系统识别底物并促进蛋白质降解。它似乎有助于调节几种癌症的进展，我们在这里表明它在胰腺癌中起肿瘤抑制作用。我们对患者组织的分析显示SPOP表达降低，这与预后不良有关。SW1990（体外/体内）和PANC-1（体外）细胞中SPOP敲低导致增殖、迁移和侵袭显著增强。SW1990细胞的共免疫沉淀实验表明，SPOP与干细胞标记物NANOG相互作用，这种相互作用最近被证明在调节前列腺癌的进展中起关键作用。我们发现，在一名胰腺癌患者中，缺乏核定位信号的SPOP截断形式（p.Q360*）的表达导致NANOG的核积累，从而促进胰腺癌细胞的生长和转移。我们的研究结果表明，SPOP通过促进NANOG的泛素化和随后的降解来抑制胰腺癌的进展。这些结果确定了SPOP-NANOG相互作用作为胰腺癌的潜在治疗靶点。
Speckle-type POZ domain protein (SPOP), an adaptor in the E3 ubiquitin ligase complex, recognizes substrates and promotes protein degradation via the ubiquitin-proteasome system. It appears to help regulate progression of several cancers, and we show here that it acts as a tumor suppressor in pancreatic cancer. Our analysis of patient tissues showed decreased SPOP expression, which was associated with poor prognosis. SPOP knockdown in SW1990 (in vitro/vivo) and PANC-1 (in vitro) cells led to significantly greater proliferation, migration, and invasion. Co-immunoprecipitation experiments in SW1990 cells showed that SPOP interacted with the stem-cell marker NANOG, and this interaction has recently been shown to play a critical role in regulating progression of prostate cancer. We showed that, in one patient with pancreatic cancer, the expression of a truncated form of SPOP (p.Q360*) lacking the nuclear localization signal led to nuclear accumulation of NANOG, which promoted growth and metastasis of pancreatic cancer cells. Our results suggest that SPOP suppresses progression of pancreatic cancer by promoting the ubiquitination and subsequent degradation of NANOG. These results identify the SPOP-NANOG interaction as a potential therapeutic target against pancreatic cancer.