Internal Ribosome Entry Sites Mediate Cap-Independent Translation of Bmi1 in Nasopharyngeal Carcinoma

Overview

Journal Front Oncol

Specialty Oncology

Date 2020 Oct 5

PMID 33014838

Citations 1

Authors

Hongbo Wang

Yunjia Zhu

Lijuan Hu

Yangyang Li

Guihong Liu

Tianliang Xia

Dan Xiong

Yiling Luo

Binliu Liu

Yu An

Manzhi Li

Yuehua Huang

Qian Zhong

Musheng Zeng

Affiliations

Soon will be listed here.

Abstract

Bmi1 is overexpressed in multiple human cancers. We previously reported the oncogenic function and the transcription regulation mechanisms of Bmi1 in nasopharyngeal carcinoma (NPC). In this study, we observed that the mRNA and the protein levels of Bmi1 were strictly inconsistent in NPC cell lines and cancer tissues. The inhibitors of proteasome and lysosome could not enhance the protein level of Bmi1, indicating that Bmi1 may be post-transcriptionally regulated. The IRESite analysis showed that there were two potential internal ribosome entry sites (IRESs) in the 5'-untranslated region (5'-UTR) of Bmi1. The luciferase assay demonstrated that the 5'-UTR of Bmi1 has IRES activity, which may mediate cap-independent translation. The IRES activity of the Bmi1 5'-UTR was significantly reduced after the mutation of the two IRES elements. Taken together, these results suggested that the IRES elements mediating translation is a novel post-transcriptional regulation mechanism of Bmi1.

Citing Articles

SFPQ promotes RAS-mutant cancer cell growth by modulating 5'-UTR mediated translational control of CK1α.

Kok V, Tang J, Ling Eng G, Tan S, Chin J, Quek C NAR Cancer. 2022; 4(3):zcac027.

PMID: 36177382 PMC: 9513841. DOI: 10.1093/narcan/zcac027.

References

Hoffman M, Palmenberg A . Mutational analysis of the J-K stem-loop region of the encephalomyocarditis virus IRES. J Virol. 1995; 69(7):4399-406. PMC: 189181. DOI: 10.1128/JVI.69.7.4399-4406.1995. View

Ochiai H, Takenobu H, Nakagawa A, Yamaguchi Y, Kimura M, Ohira M . Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1Bbeta and TSLC1 in neuroblastoma. Oncogene. 2010; 29(18):2681-90. DOI: 10.1038/onc.2010.22. View

Wang H, Zhang H, Zhang J, Li Y, Zhao B, Feng G . Neuropilin 1 is an entry factor that promotes EBV infection of nasopharyngeal epithelial cells. Nat Commun. 2015; 6:6240. PMC: 4339892. DOI: 10.1038/ncomms7240. View

Gopinath S, Malla R, Alapati K, Gorantla B, Gujrati M, Dinh D . Cathepsin B and uPAR regulate self-renewal of glioma-initiating cells through GLI-regulated Sox2 and Bmi1 expression. Carcinogenesis. 2012; 34(3):550-9. PMC: 3581601. DOI: 10.1093/carcin/bgs375. View

Cobbold L, Wilson L, Sawicka K, King H, Kondrashov A, Spriggs K . Upregulated c-myc expression in multiple myeloma by internal ribosome entry results from increased interactions with and expression of PTB-1 and YB-1. Oncogene. 2010; 29(19):2884-91. DOI: 10.1038/onc.2010.31. View

Yang J, Chai L, Liu F, Fink L, Lin P, Silberstein L . Bmi-1 is a target gene for SALL4 in hematopoietic and leukemic cells. Proc Natl Acad Sci U S A. 2007; 104(25):10494-9. PMC: 1965541. DOI: 10.1073/pnas.0704001104. View

Yadav A, Sahasrabuddhe A, Dimri M, Bommi P, Sainger R, Dimri G . Deletion analysis of BMI1 oncoprotein identifies its negative regulatory domain. Mol Cancer. 2010; 9:158. PMC: 2900245. DOI: 10.1186/1476-4598-9-158. View

Mitchell S, Spriggs K, Bushell M, Evans J, Stoneley M, Le Quesne J . Identification of a motif that mediates polypyrimidine tract-binding protein-dependent internal ribosome entry. Genes Dev. 2005; 19(13):1556-71. PMC: 1172062. DOI: 10.1101/gad.339105. View

Dutton A, Woodman C, Chukwuma M, Last J, Wei W, Vockerodt M . Bmi-1 is induced by the Epstein-Barr virus oncogene LMP1 and regulates the expression of viral target genes in Hodgkin lymphoma cells. Blood. 2006; 109(6):2597-603. DOI: 10.1182/blood-2006-05-020545. View

10.

Dimri M, Carroll J, Cho J, Dimri G . microRNA-141 regulates BMI1 expression and induces senescence in human diploid fibroblasts. Cell Cycle. 2013; 12(22):3537-46. PMC: 3906339. DOI: 10.4161/cc.26592. View

11.

Sahasrabuddhe A, Dimri M, Bommi P, Dimri G . βTrCP regulates BMI1 protein turnover via ubiquitination and degradation. Cell Cycle. 2011; 10(8):1322-30. PMC: 3117138. DOI: 10.4161/cc.10.8.15372. View

12.

Nowak K, Kerl K, Fehr D, Kramps C, Gessner C, Killmer K . BMI1 is a target gene of E2F-1 and is strongly expressed in primary neuroblastomas. Nucleic Acids Res. 2006; 34(6):1745-54. PMC: 1421501. DOI: 10.1093/nar/gkl119. View

13.

Pickering B, Mitchell S, Evans J, Willis A . Polypyrimidine tract binding protein and poly r(C) binding protein 1 interact with the BAG-1 IRES and stimulate its activity in vitro and in vivo. Nucleic Acids Res. 2003; 31(2):639-46. PMC: 140511. DOI: 10.1093/nar/gkg146. View

14.

van Galen J, Muris J, Oudejans J, Vos W, Giroth C, Ossenkoppele G . Expression of the polycomb-group gene BMI1 is related to an unfavourable prognosis in primary nodal DLBCL. J Clin Pathol. 2006; 60(2):167-72. PMC: 1860630. DOI: 10.1136/jcp.2006.038752. View

15.

Kim J, Paek K, Choi K, Kim T, Hahm B, Kim K . Heterogeneous nuclear ribonucleoprotein C modulates translation of c-myc mRNA in a cell cycle phase-dependent manner. Mol Cell Biol. 2003; 23(2):708-20. PMC: 151538. DOI: 10.1128/MCB.23.2.708-720.2003. View

16.

Hu X, Feng Y, Zhang D, Zhao S, Hu Z, Greshock J . A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. Cancer Cell. 2014; 26(3):344-357. PMC: 4159613. DOI: 10.1016/j.ccr.2014.07.009. View

17.

Komar A, Hatzoglou M . Cellular IRES-mediated translation: the war of ITAFs in pathophysiological states. Cell Cycle. 2011; 10(2):229-40. PMC: 3048795. DOI: 10.4161/cc.10.2.14472. View

18.

Liu S, Tetzlaff M, Cui R, Xu X . miR-200c inhibits melanoma progression and drug resistance through down-regulation of BMI-1. Am J Pathol. 2012; 181(5):1823-35. PMC: 3483804. DOI: 10.1016/j.ajpath.2012.07.009. View

19.

Alajez N, Shi W, Hui A, Yue S, Ng R, Lo K . Targeted depletion of BMI1 sensitizes tumor cells to P53-mediated apoptosis in response to radiation therapy. Cell Death Differ. 2009; 16(11):1469-79. DOI: 10.1038/cdd.2009.85. View

20.

Waldron T, De Dominici M, Soliera A, Audia A, Iacobucci I, Lonetti A . c-Myb and its target Bmi1 are required for p190BCR/ABL leukemogenesis in mouse and human cells. Leukemia. 2011; 26(4):644-53. PMC: 3252490. DOI: 10.1038/leu.2011.264. View