SPOP-mediated degradation of BRD4 dictates cellular sensitivity to BET inhibitors
SPOP-mediated degradation of BRD4 dictates cellular sensitivity to BET inhibitors
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DOI：
10.1080/15384101.2017.1388973
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发表时间：
2017-01-01
期刊：
影响因子：
4.3
通讯作者：
Wei, Wenyi
中科院分区：
文献类型：
--
作者：
Dai, Xiangpeng;Wang, Zhiwei;Wei, Wenyi
溴结构域和额外末端（BET）蛋白在各种人类癌症中经常过度表达，因此在临床上已被视为有吸引力的治疗性抗癌靶点。然而，对于人类癌症中 BET 异常过度表达的机制知之甚少。最近，我们报道前列腺癌衍生的 SPOP 突变体无法与 BRD4 相互作用并促进 BRD4 降解，导致 BRD4 在前列腺癌细胞中积累。因此，携带 SPOP 突变的前列腺癌细胞对 BET 抑制剂更具抵抗力。因此，我们的结果有助于通过负向控制 BET 蛋白稳定性来阐明 SPOP 在前列腺癌中的抑癌作用。更重要的是，我们的结果还为联合BET抑制剂和其他抑制剂治疗具有SPOP突变的前列腺癌患者提供了分子基础。
Bromodomain and extra-terminal (BET) proteins are frequently overexpressed in various human cancers, therefore have been clinically pursed as attractive therapeutic anti-cancer targets. However, relatively little is known about the mechanism(s) underlying aberrant BET overexpression in human cancers. Recently, we reported that prostate cancer-derived SPOP mutants fail to interact with and promote BRD4 degradation, leading to accumulation of BRD4 in prostate cancer cells. As a result, prostate cancer cells harboring SPOP mutations are more resistant to BET inhibitors. Therefore, our results help to elucidate the tumor suppressor role of SPOP in the prostate cancer setting by negatively controlling BET proteins stability. More importantly, our results also provide a molecular basis for using combination with BET inhibitors and other inhibitors to treat prostate cancer patients with SPOP mutations.