Zhang Pingzhao, Wang Dejie, Zhao Yu, Ren Shancheng, Gao Kun, Ye Zhenqing, Wang Shangqian, Pan Chun-Wu, Zhu Yasheng, Yan Yuqian, Yang Yinhui, Wu Di, He Yundong, Zhang Jun, Lu Daru, Liu Xiuping, Yu Long, Zhao Shimin, Li Yao, Lin Dong, Wang Yuzhuo, Wang Liguo, Chen Yu, Sun Yinghao, Wang Chenji, Huang Haojie
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.
Fudan University Shanghai Cancer Center and Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Nat Med. 2017 Sep;23(9):1055-1062. doi: 10.1038/nm.4379. Epub 2017 Aug 14.
Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising anticancer therapies. The gene encoding the E3 ubiquitin ligase substrate-binding adaptor speckle-type POZ protein (SPOP) is the most frequently mutated in primary prostate cancer. Here we demonstrate that wild-type SPOP binds to and induces ubiquitination and proteasomal degradation of BET proteins (BRD2, BRD3 and BRD4) by recognizing a degron motif common among them. In contrast, prostate cancer-associated SPOP mutants show impaired binding to BET proteins, resulting in decreased proteasomal degradation and accumulation of these proteins in prostate cancer cell lines and patient specimens and causing resistance to BET inhibitors. Transcriptome and BRD4 cistrome analyses reveal enhanced expression of the GTPase RAC1 and cholesterol-biosynthesis-associated genes together with activation of AKT-mTORC1 signaling as a consequence of BRD4 stabilization. Our data show that resistance to BET inhibitors in SPOP-mutant prostate cancer can be overcome by combination with AKT inhibitors and further support the evaluation of SPOP mutations as biomarkers to guide BET-inhibitor-oriented therapy in patients with prostate cancer.
溴结构域和额外末端结构域（BET）蛋白抑制剂正成为有前景的抗癌疗法。编码E3泛素连接酶底物结合适配体斑点型POZ蛋白（SPOP）的基因在原发性前列腺癌中突变最为频繁。在此我们证明，野生型SPOP通过识别BET蛋白（BRD2、BRD3和BRD4）共有的降解基序，与它们结合并诱导其泛素化和蛋白酶体降解。相反，前列腺癌相关的SPOP突变体与BET蛋白的结合受损，导致这些蛋白在前列腺癌细胞系和患者标本中的蛋白酶体降解减少和积累，并导致对BET抑制剂产生抗性。转录组和BRD4顺式作用组分析显示，由于BRD4的稳定，GTP酶RAC1和胆固醇生物合成相关基因的表达增强，同时AKT-mTORC1信号被激活。我们的数据表明，SPOP突变的前列腺癌对BET抑制剂的抗性可通过与AKT抑制剂联合使用来克服，并进一步支持将SPOP突变评估为生物标志物，以指导前列腺癌患者的BET抑制剂导向治疗。
