Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer
Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer
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DOI：
10.1073/pnas.1322198111
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发表时间：
2014-03-18
影响因子：
11.1
通讯作者：
Kittler, Ralf
中科院分区：
文献类型：
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作者：
Wang, Shan;Kollipara, Rahul K.;Kittler, Ralf
转录因子 E-26 相关基因 (ERG) 通过与雄激素反应基因跨膜蛋白酶丝氨酸 2 (TMPRSS2) 基因融合而过度表达，类似于 40% 的前列腺肿瘤，是前列腺癌发生的关键驱动因素。 ERG 的消融会破坏关键的致癌转录回路，可能是前列腺癌治疗的一种有前途的治疗策略。在这里，我们发现泛素特异性肽酶 9，X-linked (USP9X)，一种去泛素酶，在表达 TMPRSS2-ERG 的 VCaP 前列腺癌细胞中结合 ERG，并在体外使 ERG 去泛素化。 USP9X 敲除导致泛素化 ERG 水平增加，并伴有 ERG 耗竭。使用 USP9X 抑制剂 WP1130 进行治疗会导致体内和体外 ERG 降解，在微阵列分析中损害富含 ERG 和前列腺癌相关基因特征的基因表达，并抑制三种小鼠异种移植模型中 ERG 阳性肿瘤的生长。因此，我们将 USP9X 确定为前列腺癌细胞的潜在治疗靶点，并将 WP1130 确定为开发 ERG 消耗药物的先导化合物。
The transcription factor E-twenty-six related gene (ERG), which is overexpressed through gene fusion with the androgen-responsive gene transmembrane protease, serine 2 (TMPRSS2) in similar to 40% of prostate tumors, is a key driver of prostate carcinogenesis. Ablation of ERG would disrupt a key oncogenic transcriptional circuit and could be a promising therapeutic strategy for prostate cancer treatment. Here, we show that ubiquitin-specific peptidase 9, X-linked (USP9X), a deubiquitinase enzyme, binds ERG in VCaP prostate cancer cells expressing TMPRSS2-ERG and deubiquitinates ERG in vitro. USP9X knockdown resulted in increased levels of ubiquitinated ERG and was coupled with depletion of ERG. Treatment with the USP9X inhibitor WP1130 resulted in ERG degradation both in vivo and in vitro, impaired the expression of genes enriched in ERG and prostate cancer relevant gene signatures in microarray analyses, and inhibited growth of ERG-positive tumors in three mouse xenograft models. Thus, we identified USP9X as a potential therapeutic target in prostate cancer cells and established WP1130 as a lead compound for the development of ERG-depleting drugs.