New data from a kinome array study, published in the Journal of National Cancer Institute, has revealed the kinome of castration-resistant prostate cancer (CRPC) and identified kinases that are involved in Y-box-binding protein-1 (YB-1, also known as nuclease-sensitive element-binding protein 1) phosphorylation. This modification has a role in the progression of prostate cancer to castration resistance and YB-1–ribosomal s6 kinase (RSK) signalling is known to be involved in the regulation of androgen receptor (AR) splice variants.

In vitro analysis of the kinome of androgen-sensitive LNCaP and castration-resistant derivatives of LNCaP cells, called LNCaP-CxR cells, revealed that the top 30 phosphorylation sites were increased in LNCaP-CxR cells. Assessment of the phosphorylation status of these kinases showed that extracellular signal-regulated kinase (ERK)1/2 and RSK1 were hyperphosphorylated in LNCap-CxR cells. Screening revealed that YB-1 is the direct substrate of these kinases and that its phosphorylation is increased in castration-resistant cells, indicating that the ERK–RSK–YB-1 phosphorylation cascade is activated in CRPC cells.

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Investigation of other prostate cancer cell lines showed that YB-1 phosphorylation was most pronounced in castration-resistant 22Rv1 cells and this cell line was the only one to express the AR variant AR-V7. Knockdown of YBX1 significantly decreased protein and messenger RNA (mRNA) levels of AR-V7 in these cells, but had no effect on full-length AR, whereas YB-1 overexpression increased AR-V7 levels. Treatment of 22Rv1 cells with the RSK inhibitor SL0101 decreased YB-1 phosphorylation and AR-V7 protein and mRNA levels; however, levels of YB-1 and full-length AR were unaffected. Enzalutamide treatment induced RSK1 phosphorylation followed by YB-1 phosphorylation, which resulted in transcriptional increases in full-length AR and AR-V7. Combination of enzalutamide treatment with YBX1 knock down or SL0101 augmented the effects of enzalutamide on cell proliferation.

In vivo, tumours from LNCaP xenograft mouse models of progression to castration resistance showed increased YBX1 and YB-1 expression and YB-1 phosphorylation. Full-length AR and AR variant protein and mRNA levels were also increased in these tumours. Analysis of tumour samples from men with metastatic prostate cancer who had received primary androgen-deprivation therapy (ADT) showed that polymorphism in YBX1 rs12030724 is associated with YB-1 expression in prostate cancer tissues and could be a predictive biomarker for ADT.

These results suggest that YB-1 is a promising target in the quest to prevent castration resistance in prostate cancer, even when AR variants are expressed, and YBX1 polymorphism at rs12030724 could be a predictive biomarker of ADT success.