Nikhil Kumar, Raza Asif, Haymour Hanan S, Flueckiger Benjamin V, Chu Jiachong, Shah Kavita
Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA.
Cancers (Basel). 2020 Mar 12;12(3):660. doi: 10.3390/cancers12030660.
Multifunctional protein YBX1 upregulation promotes castration-resistant prostate cancer (CRPC). However, YBX1 protein abundance, but not its DNA status or mRNA levels, predicts CRPC recurrence, although the mechanism remains unknown. Similarly, the mechanism by which YBX1 regulates androgen receptor (AR) signaling remains unclear. We uncovered the first molecular mechanism of YBX1 upregulation at a post-translational level. YBX1 was identified as an Aurora Kinase-A (AURKA) substrate using a chemical screen. AURKA phosphorylates YBX1 at two key residues, which stabilizes it and promotes its nuclear translocation. YBX1 reciprocates and stabilizes AURKA, thereby initiating a synergistic loop. Notably, phospho-resistant YBX1 is dominant-negative and fully inhibits epithelial to mesenchymal transition, chemoresistance, drug-resistance and tumorigenesis in vivo. Unexpectedly, we further observed that YBX1 upregulates AR post-translationally by preventing its ubiquitylation, but not by increasing its transcription as reported before. Uncovering YBX1-mediated AR stabilization is highly significant due to AR's critical role in both androgen-sensitive prostate cancer and CRPC. As YBX1 inhibitors are unknown, AURKA inhibitors provide a potent tool to degrade both YBX1 and AR simultaneously. Finally, this is the first study to show a reciprocal loop between YBX1 and its kinase, indicating that their concomitant inhibition will be act synergistically for CRPC therapy.
多功能蛋白YBX1的上调促进去势抵抗性前列腺癌（CRPC）。然而，YBX1蛋白丰度而非其DNA状态或mRNA水平可预测CRPC复发，尽管其机制尚不清楚。同样，YBX1调节雄激素受体（AR）信号传导的机制仍不明确。我们在翻译后水平揭示了YBX1上调的首个分子机制。通过化学筛选，YBX1被鉴定为极光激酶A（AURKA）的底物。AURKA在两个关键残基处使YBX1磷酸化，这使其稳定并促进其核转位。YBX1反过来使AURKA稳定，从而启动一个协同循环。值得注意的是，磷酸抗性YBX1具有显性负性作用，可在体内完全抑制上皮-间质转化、化学抗性、耐药性和肿瘤发生。出乎意料的是，我们进一步观察到YBX1通过阻止AR的泛素化而非如之前报道的增加其转录来在翻译后上调AR。由于AR在雄激素敏感型前列腺癌和CRPC中都起着关键作用，揭示YBX1介导的AR稳定具有高度重要性。由于YBX1抑制剂尚不清楚，AURKA抑制剂提供了一种同时降解YBX1和AR的有效工具。最后，这是第一项显示YBX1与其激酶之间存在相互循环的研究，表明它们的联合抑制将在CRPC治疗中产生协同作用。
