Abstract
Prostate cancer (PCa) is one of the leading causes of cancer-related deaths in men worldwide, with over 1.4 million new cases diagnosed in the year 2020. Androgen receptor (AR) and its signalling axis has critical role not only in development and maintenance of male sex characteristics, including the normal prostate development and function, but also as a key regulator of the PCa development and its progression to castration-resistant prostate cancer (CRPC), therefore the standard of care treatment functions by directly targeting androgens/AR signalling axis using the androgen deprivation therapy (ADT). Failure of ADT and subsequent development of CRPC, where therapeutic options are very limited and mostly palliative, pose a major challenge for patients and healthcare systems around the world. The progression of the PCa disease is characterised by an abnormally increased AR activity which could result from the dysregulation of AR-associated factors (AR-AFs). Here, by using qPLEX-RIME, a state-of-the-art targeted proteomics technology, we uncover an unexpected interaction between aminoacyl-tRNA synthetases (AARSs) machinery and the androgen signalling, in which a novel non-canonical function of AARSs directly modulates AR transcriptional activity, and in return AR modulates the function of AARSs. By studying the underlying mechanism and functional implications of the AR and Aspartate-tRNA synthetase (DARS), DARS was identified as an AR-regulated gene as well as a collaborative partner of the AR leading to increased function, suggesting a feedback loop between transcription and translation. The catalytic inhibition of DARS using an aspartate mimic destabilised the AR function and induced apoptosis in PCa cell lines. We propose a novel model to help to understand the role of AR as a connecting link between transcription and translation machinery, in which non-transcriptionally active cytosolic AR has a direct role in regulating translation by modulating the canonical function of DARS, and DARS regulating the nuclear AR function, and this represents a novel therapeutic target in the treatment of PCa.
Conclusively, in this study, we have established novel reciprocal feedback between transcription and protein synthesis machinery through AR and AARSs in PCa, which could be exploited to open new treatment avenues for PCa patients.