Abstract
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.
Highlights
Prostate cancer (PCa) is one of the most common cancer among American men [1]
To confirm the data obtained from our screen, we performed an in vitro kinase assay to assess whether YBX1 was phosphorylated by Aurora Kinase A (AURKA)
We further compared AURKA-mediated YBX1 phosphorylation to another known AURKA substrate ALDH1A1 [10], both of which showed comparable phosphorylation levels (Figure 1B)
Summary
Prostate cancer (PCa) is one of the most common cancer among American men [1]. Prostate tumors can be treated effectively by radiation, medical or surgical castration. Treatment fails within a couple of years in virtually all patients, giving rise to castration-resistant prostate cancer (CRPC) [2]. Second generation androgen deprivation therapy (ADT) and chemotherapy agents have increased overall survival, but they remain palliative options. It is imperative to uncover underlying molecular mechanisms and identify effective molecular targets to prevent the progression to CRPC and/or eradicate these tumors efficiently. Aurora Kinase A (AURKA) is overexpressed in almost all PCa tumors, including CRPC [3,4,5]
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