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.

中文翻译：

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BET蛋白稳定化和AKT-mTORC1激活介导SPOP突变型前列腺癌的内在BET抑制剂耐药性。

溴结构域和末端外结构域（BET）蛋白抑制剂是有希望的抗癌治疗方法。编码E3泛素连接酶底物结合适配器斑点型POZ蛋白（SPOP）的基因在原发性前列腺癌中最常见。在这里，我们证明了野生型SPOP通过识别BET蛋白（BRD2，BRD3和BRD4）中常见的degron母体，从而结合并诱导泛素化和蛋白酶体降解。相反，与前列腺癌相关的SPOP突变体显示出与BET蛋白的结合受损，从而导致蛋白酶体降解降低以及这些蛋白在前列腺癌细胞系和患者标本中的积累，并引起对BET抑制剂的抗性。转录组和BRD4病态分析表明，由于BRD4稳定，GTPase RAC1和胆固醇生物合成相关基因的表达增强，以及AKT-mTORC1信号激活。我们的数据表明，与AKT抑制剂联用可以克服SPOP突变型前列腺癌对BET抑制剂的耐药性，并进一步支持对SPOP突变作为生物标记物的评估，以指导以BET抑制剂为导向的前列腺癌患者治疗。