SPOP targets oncogenic protein ZBTB3 for destruction to suppress endometrial cancer.
SPOP targets oncogenic protein ZBTB3 for destruction to suppress endometrial cancer.
复制标题
DOI：
10.2139/ssrn.3491871
复制
发表时间：
2019
影响因子：
5.3
通讯作者：
Xiaofeng Jin;Jian Wang;Qian Li;Zhuang Hui;Jianye Yang;Zihan Lin;Ting Lin;Zeheng Lv;Liliang Shen;Chunhong Yan;Jingfei Zheng;Jie Zhu;Zhaohui Gong;Chenji Wang;K. Gao
中科院分区：
文献类型：
--
作者：
Xiaofeng Jin;Jian Wang;Qian Li;Zhuang Hui;Jianye Yang;Zihan Lin;Ting Lin;Zeheng Lv;Liliang Shen;Chunhong Yan;Jingfei Zheng;Jie Zhu;Zhaohui Gong;Chenji Wang;K. Gao
泛素-蛋白酶体途径的失调与肿瘤的发生和发展密切相关。SPOP是基于CUL3的E3泛素连接酶复合体的接头蛋白。多项子宫内膜癌全基因组/外显子组测序研究表明，SPOP基因经常发生突变。然而，SPOP突变如何促进EC仍然知之甚少。在本研究中，转录因子ZBTB3被确定为SPOP-CUL3-RBX1 E3泛素连接酶复合体的蛋白降解底物。SPOP特异性识别位于ZBT3的两个富含Ser/Thr(S/T)的降解蛋白，并通过泛素-蛋白酶体途径启动ZBT3的降解。相比之下，EC相关的SPOP突变体在调节ZBTB3稳定性方面存在缺陷。SPOP失活部分通过ZBTB3的积聚促进子宫内膜细胞的增殖、迁移和侵袭。Sonic Hedgehog(SHH)被发现是ZBTB3的转录靶标。SPOP失活导致EC细胞中ZBTB3依赖的SHH表达上调。Ruski-43是SHH的小分子抑制剂，可抑制SPOP缺失或EC相关的SPOP突变过表达的EC细胞的增殖、迁移和侵袭。我们的数据表明，药物抑制SHH代表了一种可能的治疗SPOP突变的内皮细胞的策略。
Dysregulation of the ubiquitin-proteasome pathway is closely associated with cancer initiation and progression. SPOP is an adapter protein of the CUL3-based E3 ubiquitin ligase complexes. Several whole genome/exome sequencing studies on endometrial cancers (ECs) revealed that the SPOP gene is frequently mutated. However, how SPOP mutations contribute to EC remains poorly understood. In this study, transcription factor ZBTB3 was identified as a proteolytic substrate for the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex. SPOP specifically recognizes two Ser/Thr (S/T)-rich degrons located in ZBTB3 and triggers the degradation of ZBTB3 via the ubiquitin-proteasome pathway. By contrast, EC-associated SPOP mutants are defective in regulating ZBTB3 stability. SPOP inactivation promotes endometrial cell proliferation, migration, and invasion partly through ZBTB3 accumulation. Sonic hedgehog (SHH) was found to be a transcriptional target of ZBTB3. SPOP inactivation leads to ZBTB3-dependent SHH upregulation in EC cells. RUSKI-43, a small molecule inhibitor of SHH, suppresses cell proliferation, migration, and invasion in SPOP-depleted or EC-associated SPOP mutant-overexpressed EC cells. Our data indicate that pharmacological inhibition of SHH represents a possible treatment strategy for SPOP-mutated ECs.