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

Abstract

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.

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Fig. 1: Expression and promoter DNA methylation of EIF4A1 and its epigenetic regulation in human prostate cancer.
Fig. 2: Effect of EIF4A1 heterozygous knockout or knockdown on cell proliferation, tumor growth, and translating activity in human prostate cancer cells.
Fig. 3: Identification of eIF4A1 target mRNAs in the 5′ UTR of genes and their binding motifs in human prostate cancer cells.
Fig. 4: Relationship between expression levels of eIF4A1 protein and its potential target genes in human prostate cancer.

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Acknowledgements

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).

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Conception, design, and financial support: LW, RL. Development of methodology: CW, JL, JZ, LW, RL. Acquisition of data (bench/animal works, acquired data, etc.): CW, JL, CZ, ZL, YW, GZ, SW, XC, YZ. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): KYY, SB, LW, RL. Writing, review, and/or revision of the paper: CW, JL, KYY, LW, RL. Pathology analysis: CW, SW, LW. Study supervision: LW, RL.

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Correspondence to Lizhong Wang or Runhua Liu.

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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

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