The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3^SPOP earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.

中文翻译：

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前列腺癌相关的SPOP突变通过BRD4的稳定赋予对BET抑制剂的抗性。

蛋白质的溴结构域和末端外（BET）家族包含四个成员-BRD2，BRD3，BRD4和睾丸特异性同工型BRDT，它们主要起转录共激活子的作用，并在各种细胞过程（包括细胞周期，细胞凋亡，迁移）中发挥关键作用和入侵。BET蛋白可通过在白血病中提高这些驱动程序（例如c-Myc）的表达，或通过增强前列腺癌中诸如AR和ERG等致癌因子的转录活性来增强主要癌症驱动程序的致癌功能。病理上，BET蛋白经常过度表达，并在临床上与各种类型的人类癌症相关；因此，它们被寻求作为癌症患者选择性抑制的有吸引力的治疗靶标。为此，许多溴结构域抑制剂 已经开发出包括JQ1和I-BET在内的药物，并在早期临床试验中显示出可喜的结果。尽管在临床前模型中已记录了对BET抑制剂的抗药性，但获得抗药性的分子机制在很大程度上尚不清楚。在这里我们报告cullin-3^SPOP将BET蛋白（包括BRD2，BRD3和BRD4）用于泛素介导的降解。病理上，与前列腺癌相关的SPOP突变体不能与BET蛋白相互作用并促进其降解，从而导致其在SPOP突变型前列腺癌中的丰度升高。结果，源自具有SPOP突变的个体的前列腺癌细胞系和类器官对BET抑制剂诱导的细胞生长停滞和凋亡具有更强的抵抗力。因此，我们的结果阐明了SPOP在前列腺癌中的抑癌作用，其中它作为BET蛋白稳定性的负调节剂，还为患有SPOP突变的前列腺癌患者的BET抑制剂提供了分子机制。