Abstract
PACT (encoded by the PRKRA gene) is a double-stranded RNA binding protein that has two main functions in mammals: facilitation of antiviral defense mechanisms via the activation of protein kinase RNA (PKR) and retinoic acid-inducible gene 1 (RIG-1), and PACT is also a member of the cytoplasmic RNA-induced silencing complex. We previously described an alternate role for PACT as a modulator of nuclear receptor (NR)-regulated gene expression. Here, we investigated the role of PACT in prostate cancer (PCa) using a loss-of-function approach. Depletion of PACT in PCa cell lines resulted in a reduction in cell proliferation; however, they were viable. RNA-sequencing analysis of LNCaP PCa cells ± PACT revealed a depletion of biological processes involved in cell cycle, mitochondrial function, and NR-response pathways in the PACT knockout (KO) cells. In the PACT KO cells, downregulated genes included H2AFJ, PSMD5, AQP3, TMEM45B, SLC22A3, and KLK3 (prostate specific antigen, PSA), and siRNA mediated knockdown of these genes reduced cell growth and proliferation in LNCaP cells. Taken together, these data provide support for PRKRA as a proproliferative gene in PCa and targeting PRKRA, or the genes that are downregulated in PACT KO cells via siRNA therapies, could benefit PCa patient survival.