ADAR1 is increased in prostate cancer progression and silencing reduces A-to-I editing and cell growth while enhancing apoptosis and adhesion

Abstract Adenosine deaminase acting on RNA 1 (ADAR1) catalyses adenosine-to-inosine (A-to-I) RNA editing and has emerged as a regulator of cell biology. Here, we investigate the expression and function of ADAR1 in prostate cancer using in vitro models and clinical patient cohorts. ADAR1 was upregulated at both mRNA and protein levels across multiple prostate cancer cell lines compared to non-malignant epithelial cells; the ADAR1-p110 isoform predominantly nuclear, and ADAR1-p150 both in the nucleus and cytoplasm. ADAR1 knockdown using siRNA significantly reduced A-to-I RNA editing activity and suppressed tumour-promoting behaviours including cell growth and proliferation by reducing DNA synthesis and cell cycle progression, while enhancing apoptosis and cell-to-cell adhesion. Immunohistochemical analysis showed higher nuclear ADAR1 expression in malignant versus benign epithelium in prostatic tissue from a cohort of 230 patients with hormone-naïve localised prostate cancer undergoing radical prostatectomy. Epithelial ADAR1 expression was further associated with higher ISUP tumour grade and biochemical recurrence. Transcriptomic and proteomic analyses demonstrated increased ADAR1 expression in metastatic prostate cancer, including castration-resistant bone and lymph node lesions. Together, these findings highlight ADAR1 as a key modulator of RNA editing and cell behaviour in prostate cancer and support its potential as a novel therapeutic target.