Aurora Kinase A-YBX1 Synergy Fuels Aggressive Oncogenic Phenotypes and Chemoresistance in Castration-Resistant Prostate Cancer

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.

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

“…Likewise, NEDD9 [9] and PUM2 [13] not only stimulate autophosphorylation and autoactivation of AURKA but also stabilize AURKA protein expression through disassociation from cdh. AURKA protein stability is also maintained by Twist [15], ALDH1A1 [16], YBX1 [17] and the deubiquitinase USP2a [18] through ubiquitin-proteosomal degradation pathway. Negative regulators of AURKA Although many proteins determine the active state of AURKA to a great extent, negative AURKA regulators that tightly control AURKA expression or activity exist.…”

“…SOX2 and YBX1 are oncogenic transcription factors phosphorylated by AURKA. After phosphorylation, SOX2 is able to maintain the ratio of stem cell-like cells, while YBX1 is stabilized and enhances EMT, stem cell formation and chemoresistance [17,64]. LDHB is a subunit of the tetrameric enzyme LDH that catalyzes the interconversion between pyruvate and lactate.…”

OTUD6A Is an Aurora Kinase A-Specific Deubiquitinase

“…On the other hand, the expression of Aurora-A itself is directly regulated by transcription factors including FOXM1, ARID3A, E4TF1, and SIX3 [ 46 , 47 , 48 , 49 ] and non-DUB molecules such as Twist, YBX1, and ALDH1A1 have been shown to inhibit proteolysis of Aurora-A through the positive feedback loop with Aurora-A. However, the molecular mechanism by which Aurora-A is stabilized is unclear [ 37 , 50 , 51 ].…”

Dual-Inhibitors of N-Myc and AURKA as Potential Therapy for Neuroendocrine Prostate Cancer

“…While CYC-116 was terminated in phase 1 trial, Danusertib, although well tolerated by patients with advanced or metastatic solid tumors, only showed minimal efficacy in patients with metastatic CRPC [44,45]. Unfortunately, none of the proposed AKIs have been approved for clinical use yet due to many of them showing adverse effects in clinical trials, highlighting the difficulty in designing inhibitors with high specificity and potency to Aurora kinases [46].…”