SPOP promotes CREB5 ubiquitination to inhibit MET signaling in liver cancer

De-ao Gong, Peng Zhou, Wen-yi Chang, Jia-yao Yang, Yan-lai Zhang, Ai-long Huang, Ni Tang, Kai Wang

Abstract

Liver cancer is ranked as the sixth most prevalent from of malignancy globally and stands as the third primary contributor to cancer-related mortality. Metastasis is the main reason for liver cancer treatment failure and patient deaths. Speckle-type POZ protein (SPOP) serves as a crucial substrate junction protein within the cullin-RING E3 ligase complex, acting as a significant tumor suppressor in liver cancer. Nevertheless, the precise molecular mechanism underlying the role of SPOP in liver cancer metastasis remain elusive. In the current study, we identified cAMP response element binding 5 (CREB5) as a novel SPOP substrate in liver cancer. SPOP facilitates non-degradative K63-polyubiquitination of CREB5 on K432 site, consequently hindering its capacity to activate receptor tyrosine kinase MET. Moreover, liver cancer-associated SPOP mutant S119N disrupts the SPOP-CREB5 interactions and impairs the ubiquitination of CREB5.This disruption ultimately leads to the activation of the MET signaling pathway and enhances metastatic properties of hepatoma cells both in vitro and in vivo. In conclusion, our findings highlight the functional significance of the SPOP-CREB5-MET axis in liver cancer metastasis.

DOI:  https://doi.org/10.1016/j.bbamcr.2023.119642

Full text: https://www.sciencedirect.com/science/article/abs/pii/S016748892300215X 

SPOP通过泛素化CREB5调控MET信号抑制肝癌转移

龚德敖，周鹏，常文译，杨佳瑶，张彦来，黄爱龙，唐霓，汪凯

（重庆医科大学第二附属医院 病毒性肝炎研究所 感染性疾病分子生物学教育部重点实验室）

摘要：肝癌仍是全球重大公共卫生问题，其发病率居世界第六位，死亡率居世界第三位。肝癌的复发和转移是导致肝癌患者治疗失败和死亡的主要原因。斑点型锌指结构蛋白（speckle-type POZ protein, SPOP）是Cullin-RING E3泛素连接酶复合物中一个重要的底物接头蛋白，在肝癌中发挥了重要的肿瘤抑制因子作用。然而，SPOP抑制肝癌转移的确切分子机制仍有待阐明。在本研究中，我们首次发现在肝癌中 cAMP 反应元件结合蛋白5（cAMP responsive element binding protein 5, CREB5）是SPOP的一种新型底物蛋白。SPOP促进了CREB5蛋白 K63连接的非降解型泛素化，并且CREB5第432位赖氨酸（K432）是SPOP的主要泛素化位点。CREB5的泛素化修饰抑制了其激活受体酪氨酸激酶MET的能力。此外，肝癌相关的SPOP突变体SPOP-S119N破坏了其与CREB5之间的相互作用，并抑制了CREB5的泛素化，最终导致MET信号通路的激活，增强了肝癌细胞在体外和体内的侵袭和迁移能力。总之，我们的研究结果揭示了SPOP-CREB5-MET轴在肝癌转移中的重要作用，为肝癌的治疗提供了一种潜在的新策略。

关键词：肝癌；斑点型锌指结构蛋白；泛素化；cAMP 反应元件结合蛋白5；肿瘤转移