LAPSE:2018.0332
Published Article
LAPSE:2018.0332
ADAR Mediated RNA Editing Modulates MicroRNA Targeting in Human Breast Cancer
Justin T. Roberts, Dillon G. Patterson, Valeria M. King, Shivam V. Amin, Caroline J. Polska, Dominika Houserova, Aline Crucello, Emmaline C. Barnhill, Molly M. Miller, Timothy D. Sherman, Glen M. Borchert
July 31, 2018
RNA editing by RNA specific adenosine deaminase acting on RNA (ADAR) is increasingly being found to alter microRNA (miRNA) regulation. Editing of miRNA transcripts can affect their processing, as well as which messenger RNAs (mRNAs) they target. Further, editing of target mRNAs can also affect their complementarity to miRNAs. Notably, ADAR editing is often increased in malignancy with the effect of these RNA changes being largely unclear. In addition, numerous reports have now identified an array of miRNAs that directly contribute to various malignancies although the majority of their targets remain largely undefined. Here we propose that modulating the targets of miRNAs via mRNA editing is a frequent occurrence in cancer and an underappreciated participant in pathology. In order to more accurately characterize the relationship between these two regulatory processes, this study examined RNA editing events within mRNA sequences of two breast cancer cell lines (MCF-7 and MDA-MB-231) and determined whether or not these edits could modulate miRNA associations. Computational analyses of RNA-Seq data from these two cell lines identified over 50,000 recurrent editing sites within human mRNAs, and many of these were located in 3′ untranslated regions (UTRs). When these locations were screened against the list of currently-annotated miRNAs we discovered that editing caused a subset (~9%) to have significant alterations to mRNA complementarity. One miRNA in particular, miR-140-3p, is known to be misexpressed in many breast cancers, and we found that mRNA editing allowed this miRNA to directly target the apoptosis inducing gene DFFA in MCF-7, but not in MDA-MB-231 cells. As these two cell lines are known to have distinct characteristics in terms of morphology, invasiveness and physiological responses, we hypothesized that the differential RNA editing of DFFA in these two cell lines could contribute to their phenotypic differences. Indeed, we confirmed through western blotting that inhibiting miR-140-3p increases expression of the DFFA protein product in MCF-7, but not MDA-MB-231, and further that inhibition of miR-140-3p also increases cellular growth in MCF-7, but not MDA-MB-231. Broadly, these results suggest that the creation of miRNA targets may be an underappreciated function of ADAR and may help further elucidate the role of RNA editing in tumor pathogenicity.
Keywords
ADAR, breast, cancer, inosine, microRNA, microRNA targeting, RNA editing
Subject
Suggested Citation
Roberts JT, Patterson DG, King VM, Amin SV, Polska CJ, Houserova D, Crucello A, Barnhill EC, Miller MM, Sherman TD, Borchert GM. ADAR Mediated RNA Editing Modulates MicroRNA Targeting in Human Breast Cancer. (2018). LAPSE:2018.0332
Author Affiliations
Roberts JT: Department of Biology, University of South Alabama, Mobile, AL 36688-0002, USA [ORCID]
Patterson DG: Department of Biology, University of South Alabama, Mobile, AL 36688-0002, USA
King VM: Department of Biology, University of South Alabama, Mobile, AL 36688-0002, USA
Amin SV: Department of Biology, University of South Alabama, Mobile, AL 36688-0002, USA
Polska CJ: Department of Biology, University of South Alabama, Mobile, AL 36688-0002, USA
Houserova D: Department of Pharmacology, USA College of Medicine, Mobile, AL 36688-0002, USA
Crucello A: Department of Biology, University of South Alabama, Mobile, AL 36688-0002, USA
Barnhill EC: Department of Biology, University of South Alabama, Mobile, AL 36688-0002, USA
Miller MM: Department of Biology, University of South Alabama, Mobile, AL 36688-0002, USA
Sherman TD: Department of Biology, University of South Alabama, Mobile, AL 36688-0002, USA
Borchert GM: Department of Biology, University of South Alabama, Mobile, AL 36688-0002, USA; Department of Pharmacology, USA College of Medicine, Mobile, AL 36688-0002, USA [ORCID]
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Journal Name
Processes
Volume
6
Issue
5
Article Number
E42
Year
2018
Publication Date
2018-04-25
Published Version
ISSN
2227-9717
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PII: pr6050042, Publication Type: Journal Article
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LAPSE:2018.0332
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doi:10.3390/pr6050042
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Jul 31, 2018
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