Second-Generation HSP90 Inhibitor Onalespib Blocks mRNA Splicing of Androgen Receptor Variant 7 in Prostate Cancer Cells.
Second-Generation HSP90 Inhibitor Onalespib Blocks mRNA Splicing of Androgen Receptor Variant 7 in Prostate Cancer Cells.
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DOI：
10.1158/0008-5472.can-15-2186
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发表时间：
2016-05-01
期刊：
影响因子：
11.2
通讯作者：
de Bono JS
中科院分区：
文献类型：
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作者：
Ferraldeschi R;Welti J;Powers MV;Yuan W;Smyth T;Seed G;Riisnaes R;Hedayat S;Wang H;Crespo M;Nava Rodrigues D;Figueiredo I;Miranda S;Carreira S;Lyons JF;Sharp S;Plymate SR;Attard G;Wallis N;Workman P;de Bono JS
在前列腺癌中对可用激素疗法的抗性与雄激素受体（AR）的选择性剪接相关，并且具体地，与截短的和组成型活性的AR变体7（AR-V7）的表达相关。类固醇受体（包括AR）的转录活性依赖于与HSP 90伴侣机制的相互作用，但目前尚不清楚HSP 90是否调节AR变体的活性或表达。在这里，我们研究了HSP 90抑制对内源性表达该变体的前列腺癌细胞系中AR-V7的影响。我们证明，AR-V7和全长AR（AR-FL）被耗尽后抑制HSP 90。然而，AR-V7耗竭的机制与AR-FL不同，而HSP 90抑制使AR-FL不稳定并诱导其蛋白酶体降解，AR-V7蛋白表现出比AR-FL更高的稳定性，并且不需要HSP 90伴侣活性。相反，HSP 90抑制导致AR-V7 mRNA水平降低，但不影响总AR转录水平，表明HSP 90抑制破坏了AR-V7剪接。对全转录组RNA测序数据的生物信息学分析证实，第二代HSP 90抑制剂onalb改变了前列腺癌细胞中至少557个基因的剪接，包括AR。这些发现表明，HSP 90抑制对mRNA剪接的影响可能在表达AR-V7的前列腺癌中证明是有益的，支持HSP 90抑制剂在对雄激素剥夺不再有反应的恶性肿瘤中的进一步临床研究。
Resistance to available hormone therapies in prostate cancer has been associated with alternative splicing of androgen receptor (AR), and specifically, the expression of truncated and constitutively active AR variant 7 (AR-V7). The transcriptional activity of steroid receptors, including AR, is dependent on interactions with the HSP90 chaperone machinery, but it is unclear if HSP90 modulates the activity or expression of AR variants. Here, we investigated the effects of HSP90 inhibition on AR-V7 in prostate cancer cell lines endogenously expressing this variant. We demonstrate that AR-V7 and full-length AR (AR-FL) were depleted upon inhibition of HSP90. However, the mechanisms underlying AR-V7 depletion differed from those for AR-FL. Whereas HSP90 inhibition destabilized AR-FL and induced its proteasomal degradation, AR-V7 protein exhibited higher stability than AR-FL and did not require HSP90 chaperone activity. Instead, HSP90 inhibition resulted in the reduction of AR-V7 mRNA levels, but did not affect total AR transcript levels, indicating that HSP90 inhibition disrupted AR-V7 splicing. Bioinformatic analyses of transcriptome-wide RNA sequencing data confirmed that the second-generation HSP90 inhibitor onalespib altered the splicing of at least 557 genes in prostate cancer cells, including AR. These findings indicate that the effects of HSP90 inhibition on mRNA splicing may prove beneficial in prostate cancers expressing AR-V7, supporting further clinical investigation of HSP90 inhibitors in malignancies no longer responsive to androgen deprivation.