Yuan Dong, Chen Yiyu, Yang Zhu, Li Gang, Wu Mingjun, Jiang Jinyue, Li Dan, Yu Qiubo
Department of Gynecology, The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010, P. R. China.
Molecular Medical Laboratory, Institute of Life Sciences, Chongqing Medical University Chongqing 400016, P. R. China.
Am J Cancer Res. 2020 Aug 1;10(8):2428-2445. eCollection 2020.
Speckle-type POZ protein (SPOP), a novel cancer- associated protein, was previously reported to function as a tumor suppressor or promoter in different malignant tumors. This research aims to investigate the biological functions and underlying molecular mechanisms of SPOP in choriocarcinoma. Our analysis of patient tissues and cell lines showed significantly decreased SPOP expression and highly expressed Nuclear DNA helicase II and RNA helicase A (DHX9), both of them are mainly located into the nucleus. Induction or depletion of endogenous SPOP with a lentivirus-based system correspondingly suppressed or promoted migration and invasion of choriocarcinoma cells. Mechanistically, we found that SPOP bound to DHX9 and induced the ubiquitination and degradation of DHX9 by recognizing a typical SPOP-binding motif in DHX9. SPOP-DHX9 interaction was demonstrated to play a critical role in regulating migration and invasion abilities of choriocarcinoma cells, the promotion of mobility ability in knocking down SPOP was partly counteracted by transfection with siRNA against DHX9. Taken together, our results suggest that SPOP suppresses migration and invasion of choriocarcinoma by promoting the ubiquitination and subsequent degradation of DHX9, which identifies the SPOP-DHX9 interaction may serve as a potential therapeutic target against choriocarcinoma.
斑点型POZ蛋白（SPOP）是一种新型的癌症相关蛋白，此前有报道称其在不同的恶性肿瘤中发挥肿瘤抑制或促进作用。本研究旨在探讨SPOP在绒毛膜癌中的生物学功能及潜在分子机制。我们对患者组织和细胞系的分析显示，SPOP表达显著降低，而核DNA解旋酶II和RNA解旋酶A（DHX9）高表达，它们都主要定位于细胞核。利用基于慢病毒的系统对内源SPOP进行诱导或缺失，相应地抑制或促进了绒毛膜癌细胞的迁移和侵袭。机制上，我们发现SPOP与DHX9结合，并通过识别DHX9中典型的SPOP结合基序诱导DHX9的泛素化和降解。SPOP-DHX9相互作用被证明在调节绒毛膜癌细胞的迁移和侵袭能力中起关键作用，敲低SPOP后迁移能力的增强部分被针对DHX9的小干扰RNA转染所抵消。综上所述，我们的结果表明，SPOP通过促进DHX9的泛素化及随后的降解来抑制绒毛膜癌的迁移和侵袭，这表明SPOP-DHX9相互作用可能成为抗绒毛膜癌的潜在治疗靶点。
