In prostate cancers, elongation initiation factor 4A1 (eIF4A1) supports an oncogenic translation program and is highly expressed, but its role remains elusive. By the use of human specimens and cell models, we 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, we characterized, in human prostate cancer cells, the epigenetic regulation of EIF4A1 transcripts through DNA methylation in the CpG-rich island of EIF4A1. Next, we investigated the oncogenic effect of EIF4A1 on cancer cell proliferation in vitro and tumor growth in vivo. For prostate cancer cells, EIF4A1 heterozygous knockout or knockdown inhibited protein translation and tumor growth. In addition, using RNA immunoprecipitation with RNA sequencing, we 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, we found a positive correlation between expression levels of eIF4A1 and BRD2 in primary prostate cancers. Our results demonstrate, for prostate cancer cells, epigenetic regulation of EIF4A1 transcripts through DNA methylation and an oncogenic role of eIF4A1 through BRD2 signaling.
This is a preview of subscription content, access via your institution
Subscribe to Journal
Get full journal access for 1 year
only $2.38 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Malina A, Mills JR, Pelletier J. Emerging therapeutics targeting mRNA translation. Cold Spring Harb Perspect Biol. 2012;4:a012377.
Ramamurthy VP, Ramalingam S, Kwegyir-Afful AK, Hussain A, Njar VC. Targeting of protein translation as a new treatment paradigm for prostate cancer. Curr Opin Oncol. 2017;29:210–20.
Jackson RJ, Hellen CU, Pestova TV. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol. 2010;11:113–27.
Sonenberg N, Hinnebusch AG. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell. 2009;136:731–45.
Wolfe AL, Singh K, Zhong Y, Drewe P, Rajasekhar VK, Sanghvi VR, et al. RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature. 2014;513:65–70.
Schrecengost R, Knudsen KE. Molecular pathogenesis and progression of prostate cancer. Semin Oncol. 2013;40:244–58.
Waldron JA, Tack DC, Ritchey LE, Gillen SL, Wilczynska A, Turro E, et al. mRNA structural elements immediately upstream of the start codon dictate dependence upon eIF4A helicase activity. Genome Biol. 2019;20:300.
Chan K, Robert F, Oertlin C, Kapeller-Libermann D, Avizonis D, Gutierrez J, et al. eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma. Nat Commun. 2019;10:5151.
Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature. 2014;510:278–82.
Faivre EJ, McDaniel KF, Albert DH, Mantena SR, Plotnik JP, Wilcox D, et al. Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer. Nature. 2020;578:306–10.
Muhar M, Ebert A, Neumann T, Umkehrer C, Jude J, Wieshofer C, et al. SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis. Science. 2018;360:800–5.
Kregel S, Malik R, Asangani IA, Wilder-Romans K, Rajendiran T, Xiao L, et al. Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer. Clin Cancer Res. 2019;25:4038–48.
Dang CV. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol. 1999;19:1–11.
Dang CV, O’Donnell KA, Zeller KI, Nguyen T, Osthus RC, Li F. The c-Myc target gene network. Semin Cancer Biol. 2006;16:253–64.
Remondini D, O’Connell B, Intrator N, Sedivy JM, Neretti N, Castellani GC, et al. Targeting c-Myc-activated genes with a correlation method: detection of global changes in large gene expression network dynamics. Proc Natl Acad Sci USA. 2005;102:6902–6.
Ellwood-Yen K, Graeber TG, Wongvipat J, Iruela-Arispe ML, Zhang J, Matusik R, et al. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell. 2003;4:223–38.
Zeller KI, Jegga AG, Aronow BJ, O’Donnell KA, Dang CV. An integrated database of genes responsive to the Myc oncogenic transcription factor: identification of direct genomic targets. Genome Biol. 2003;4:R69.
Kumar A, Vaish M, Karuppagounder SS, Gazaryan I, Cave JW, Starkov AA, et al. HIF1alpha stabilization in hypoxia is not oxidant-initiated. Elife. 2021;10:e72873.
De Benedetti A, Graff JR. eIF-4E expression and its role in malignancies and metastases. Oncogene. 2004;23:3189–99.
Modelska A, Turro E, Russell R, Beaton J, Sbarrato T, Spriggs K, et al. The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape. Cell Death Dis. 2015;6:e1603.
de la Parra C, Walters BA, Geter P, Schneider RJ. Translation initiation factors and their relevance in cancer. Curr Opin Genet Dev. 2018;48:82–88.
Raman D, Tiwari AK. Role of eIF4A1 in triple-negative breast cancer stem-like cell-mediated drug resistance. Cancer Rep (Hoboken). 2020;14:e1299.
Sridharan S, Robeson M, Bastihalli-Tukaramrao D, Howard CM, Subramaniyan B, Tilley AMC, et al. Targeting of the Eukaryotic Translation Initiation Factor 4A Against Breast Cancer Stemness. Front Oncol. 2019;9:1311.
Gao C, Guo X, Xue A, Ruan Y, Wang H, Gao X. High intratumoral expression of eIF4A1 promotes epithelial-to-mesenchymal transition and predicts unfavorable prognosis in gastric cancer. Acta Biochim Biophys Sin (Shanghai). 2020;52:310–9.
Quinn CM, Wiles AP, El-Shanawany T, Catchpole I, Alnadaf T, Ford MJ, et al. The human eukaryotic initiation factor 4AI gene (EIF4A1) contains multiple regulatory elements that direct high-level reporter gene expression in mammalian cell lines. Genomics. 1999;62:468–76.
Waldron JA, Raza F, Le Quesne J. eIF4A alleviates the translational repression mediated by classical secondary structures more than by G-quadruplexes. Nucleic Acids Res. 2018;46:3075–87.
Malka-Mahieu H, Newman M, Desaubry L, Robert C, Vagner S. Molecular Pathways: The eIF4F Translation Initiation Complex-New Opportunities for Cancer Treatment. Clin Cancer Res. 2017;23:21–5.
Leppek K, Das R, Barna M. Functional 5’ UTR mRNA structures in eukaryotic translation regulation and how to find them. Nat Rev Mol Cell Biol. 2018;19:158–74.
Rubio CA, Weisburd B, Holderfield M, Arias C, Fang E, DeRisi JL, et al. Transcriptome-wide characterization of the eIF4A signature highlights plasticity in translation regulation. Genome Biol. 2014;15:476.
Jin C, Rajabi H, Rodrigo CM, Porco JA Jr, Kufe D. Targeting the eIF4A RNA helicase blocks translation of the MUC1-C oncoprotein. Oncogene. 2013;32:2179–88.
Urbanucci A, Barfeld SJ, Kytola V, Itkonen HM, Coleman IM, Vodak D, et al. Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer. Cell Rep. 2017;19:2045–59.
Liu XS, Wu H, Ji X, Stelzer Y, Wu X, Czauderna S, et al. Editing DNA Methylation in the Mammalian Genome. Cell. 2016;167:233–247 e217.
Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9:R137.
Feng J, Liu T, Qin B, Zhang Y, Liu XS. Identifying ChIP-seq enrichment using MACS. Nat Protoc. 2012;7:1728–40.
Yu G, Wang LG, He QY. ChIPseeker: an R/Bioconductor package for ChIP peak annotation, comparison and visualization. Bioinformatics. 2015;31:2382–3.
We thank Dr Donald Hill for editorial assistance in preparing this paper. This work was supported by grants from the Department of Defense (W81XWH-15-1-0323 and W81XWH-20-1-0426 for RL and W81XWH-21-1-0100 for LW), the National Cancer Institute (CA118948 for LW), and the Mike Slive Foundation for Prostate Cancer Research (RL).
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Wang, C., Leavenworth, J., Zhang, C. et al. Epigenetic regulation of EIF4A1 through DNA methylation and an oncogenic role of eIF4A1 through BRD2 signaling in prostate cancer. Oncogene 41, 2778–2785 (2022). https://doi.org/10.1038/s41388-022-02272-3