Emerging evidence associates translation factors and regulators to tumorigenesis. Recent advances in our ability to perform global translatome analyses indicate that our understanding of translational changes in cancer resistance is still limited. Here, we generated an enzalutamide-resistant prostate cancer (PCa) model, which recapitulated key features of clinical enzalutamide-resistant PCa. Using this model and polysome profiling, we investigated global translation changes that occur during the acquisition of PCa resistance. We found that enzalutamide-resistant cells exhibit a discordance in biological pathways affected in their translatome relative to their transcriptome, a deregulation of proteins involved in translation, and an overall decrease in translational efficiency. We also show that genomic alterations in proteins with high translational efficiency in enzalutamide-resistant cells are good predictors of poor patient prognosis. Additionally, long non-coding RNAs in enzalutamide-resistant cells show increased association with ribosomes, higher translation efficiency, and an even stronger correlation with poor patient prognosis. Taken together, this suggests that aberrant translation of coding and non-coding genes are strong indicators of PCa enzalutamide-resistance. Our findings thus point towards novel therapeutic avenues that may target enzalutamide resistant PCa.

中文翻译：

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前列腺癌耐药性导致翻译因子的全球失调和长非编码 RNA 的非常规翻译

新出现的证据将翻译因子和调节因子与肿瘤发生联系起来。我们进行全局翻译组分析能力的最新进展表明，我们对癌症抗性的翻译变化的理解仍然有限。在这里，我们生成了一个恩杂鲁胺耐药前列腺癌 (PCa) 模型，该模型概括了临床恩杂鲁胺耐药 PCa 的关键特征。使用此模型和 polysome 分析，我们调查了在获得 PCa 抗性期间发生的全局翻译变化。我们发现，耐enzalutamide的细胞在其转录组相对于其转录组受到影响的生物学途径中表现出不一致，使参与翻译的蛋白质失调，并且翻译效率总体下降。我们还表明，在恩杂鲁胺耐药细胞中具有高转化效率的蛋白质的基因组改变是患者预后不良的良好预测因子。此外，恩杂鲁胺耐药细胞中的长链非编码 RNA 与核糖体的关联增加、翻译效率更高，并且与患者预后不良的相关性更强。两者合计，这表明编码和非编码基因的异常翻译是PCa enzalutamide抗性的有力指标。因此，我们的研究结果指向了可能针对恩杂鲁胺耐药 PCa 的新治疗途径。并且与患者预后不良的相关性更强。总之，这表明编码和非编码基因的异常翻译是 PCa 恩杂鲁胺抗性的有力指标。因此，我们的研究结果指向了可能针对恩杂鲁胺耐药 PCa 的新治疗途径。并且与患者预后不良的相关性更强。总之，这表明编码和非编码基因的异常翻译是 PCa 恩杂鲁胺抗性的有力指标。因此，我们的研究结果指向了可能针对恩杂鲁胺耐药 PCa 的新治疗途径。