Epigenetic regulation of <i>EIF4A1</i> through DNA methylation and an oncogenic role of eIF4A1 through BRD2 signaling in prostate cancer

In prostate cancers, elongation initiation factor 4A1 (eIF4A1) supports an oncogenic translation program and is highly expressed, but its role remains elusive. Using human specimens and cell models, the study addressed the role of eIF4A1 in prostate cancer in vitro and in vivo. EIF4A1 expression, as determined by mRNA and protein levels, was higher in primary prostate cancers relative to normal prostate tissue. Also, for primary prostate cancers, elevated mRNA levels of EIF4A1 correlated with DNA hypomethylation levels in the CpG-rich island of EIF4A1. Using a DNMT3a CRISPR-Cas9-based tool for specific targeting of DNA methylation, the study characterized, in human prostate cancer cells, the epigenetic regulation of EIF4A1 transcripts through DNA methylation in the CpG-rich island of EIF4A1. Next, the study investigated the oncogenic effect of EIF4A1 on cancer cell proliferation in vitro and tumor growth in vivo. EIF4A1 heterozygous knockout or knockdown inhibited protein translation and tumor growth for prostate cancer cells. In addition, using RNA immunoprecipitation with RNA sequencing, the authors discovered the eIF4A1-mediated translational regulation of the oncogene BRD2, which contains the most enriched eIF4A1-binding motifs in its 5′ untranslated region, establishing an eIF4A1-BRD2 axis for oncogenic translation. Finally, the study found a positive correlation between expression levels of eIF4A1 and BRD2 in primary prostate cancers. The study results demonstrate, for prostate cancer cells, epigenetic regulation of EIF4A1 transcripts through DNA methylation and an oncogenic role of eIF4A1 through BRD2 signaling.