FLI1 promotes protein translation via the transcriptional regulation of MKNK1 expression

Wang,Chunlin; Song,Jialei; Liu,Wuling; Yao,Yao; Kapranov,Philipp; Sample,Klarke  M.; Gajendran,Babu; Zacksenhaus,Eldad; Hao,Xiaojiang; Ben‑David,Yaacov

doi:10.3892/ijo.2019.4943

FLI1 promotes protein translation via the transcriptional regulation of MKNK1 expression

Authors:
- Chunlin Wang
- Jialei Song
- Wuling Liu
- Yao Yao
- Philipp Kapranov
- Klarke M. Sample
- Babu Gajendran
- Eldad Zacksenhaus
- Xiaojiang Hao
- Yaacov Ben‑David
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Affiliations: State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Province Science City, High Tech Zone, Baiyun, Guiyang, Guizhou 550014, P.R. China, Institute of Genomics, School of Biomedical Sciences, Huaqiao University, Xiamen, Fujian 361021, P.R. China, Central Laboratory, Guizhou Provincial People's Hospital, The Affiliated Hospital of Guizhou University Medical College, Guiyang, Guizhou 550002, P.R. China, Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
Published online on: December 16, 2019 https://doi.org/10.3892/ijo.2019.4943
Pages: 430-438
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The disruption of protein translation machinery is a common feature of cancer initiation and progression, and drugs that target protein translation offer new avenues for therapy. The translation initiation factor, eukaryotic initiation factor 4E (eIF4E), is induced in a number of cancer cell lines and is one such candidate for therapeutic intervention. Friend leukemia integration 1 (FLI1) is a potent oncogenic transcription factor that promotes various types of cancer by promoting several hallmarks of cancer progression. FLI1 has recently been implicated in protein translation through yet unknown mechanisms. This study identified a positive association between FLI1 expression and mitogen‑activated protein kinase (MAPK)‑interacting serine/threonine kinase1 (MKNK1), the immediate upstream regulator of the eIF4E initiation factor. The short hairpin RNA (shRNA)‑mediated silencing or overexpression of FLI1 in leukemic cell lines downregulated or upregulated MKNK1 expression, respectively. Promoter analysis identified a potent FLI1 binding site in the regulatory region of the MKNK1 promoter. In transient transfection experiments, FLI1 increased MKNK1 promoter activity, which was blocked by mutating the FLI1 binding site. FLI1 specifically affected the expression of MKNK1, but not that of MKNK2. The siRNA‑mediated downregulation of MKNK1 downregulated the expression of survivin (BIRC5) and significantly suppressed cell proliferation in culture. FLI1 inhibitory compounds were shown to downregulate this oncogene through the suppression of MAPK/extracellular‑regulated kinase (ERK) signaling and the subsequent activation of miR‑145, leading to a lower MKNK1 expression and the suppression of leukemic growth. These results uncover a critical role for FLI1 in the control of protein translation and the importance of targeting its function and downstream mediators, such as MKNK1, for cancer therapy.

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