Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4.
Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4.
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DOI：
10.1038/nm.4378
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发表时间：
2017-09
期刊：
影响因子：
82.9
通讯作者：
Wei W
中科院分区：
文献类型：
--
作者：
Dai X;Gan W;Li X;Wang S;Zhang W;Huang L;Liu S;Zhong Q;Guo J;Zhang J;Chen T;Shimizu K;Beca F;Blattner M;Vasudevan D;Buckley DL;Qi J;Buser L;Liu P;Inuzuka H;Beck AH;Wang L;Wild PJ;Garraway LA;Rubin MA;Barbieri CE;Wong KK;Muthuswamy SK;Huang J;Chen Y;Bradner JE;Wei W
BET蛋白家族由BRD2、BRD3、BRD4和睾丸特异性异构体BRDT四个成员组成，主要作为转录共激活因子发挥作用，在细胞周期、细胞凋亡、迁移和侵袭等多种细胞过程中发挥重要作用。因此，BET蛋白通过提高其在白血病中的表达(如c-Myc)或通过在前列腺癌环境中促进致癌因子(如AR和ERG)的转录活性来增强主要癌症驱动因素的致癌功能。在病理学上，BET蛋白经常过度表达，并在临床上与各种类型的人类癌症有关，因此被认为是患者选择性抑制的有吸引力的治疗靶点。为此，已经开发了一些溴域抑制剂，包括JQ1和I-BET，并在早期临床试验中显示了良好的结果。尽管在临床前模型中已经记录了对BET抑制剂的耐药性，但获得性耐药性背后的分子机制在很大程度上是未知的。在这里，我们报告了cullin 3SPOP专门标记BET蛋白，包括BRD2，BRD3和BRD4，用于泛素化介导的降解。病理上，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破坏，导致SPOP缺陷前列腺癌中BET蛋白的丰度增加。因此，含有SPOP突变的前列腺癌细胞和前列腺癌患者衍生的有机物对BET抑制剂诱导的细胞生长停滞和凋亡更具抵抗力。因此，我们的结果阐明了SPOP通过负向控制BET蛋白稳定性在前列腺癌中的抑癌作用，也为携带SPOP突变的前列腺癌患者BET抑制剂耐药提供了分子机制。
The bromodomain and extra-terminal (BET) family of proteins, comprised of four members including BRD2, BRD3, BRD4 and the testis-specific isoform BRDT, largely function as transcriptional co-activators and play critical roles in various cellular processes, including cell cycle, apoptosis, migration and invasion . As such, BET proteins enhance the oncogenic functions of major cancer drivers by either elevating their expression such as c-Myc in leukemia or by promoting transcriptional activities of oncogenic factors such as AR and ERG in the prostate cancer setting . Pathologically, BET proteins are frequently overexpressed and clinically linked to various types of human cancers , therefore pursued as attractive therapeutic targets for selective inhibition in patients. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed and shown promising outcomes in early clinical trials. Despite resistance to BET inhibitor has been documented in pre-clinical models the molecular mechanisms underlying acquired resistance are largely unknown. Here, we report that Cullin 3SPOP 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 destruction of BET proteins, leading to their elevated abundance in SPOP-deficient prostate cancer. As a result, prostate cancer cells and prostate cancer patient-derived organoids 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 by negatively controlling BET protein stability, and also provide a molecular mechanism for BET inhibitor resistance in prostate cancer patients bearing SPOP mutations.
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影响因子：
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