Thorne, JL orcid.org/0000-0002-3037-8528, Battaglia, S, Baxter, DE orcid.org/0000-0001-8830-6802 et al. (8 more authors) (2018) MiR-19b non-canonical binding is directed by HuR and confers chemosensitivity through regulation of P-glycoprotein in breast cancer. BBA - Gene Regulatory Mechanisms, 1861 (11). pp. 996-1006. ISSN 1874-9399
Abstract
MicroRNAs and RNA-binding proteins exert regulation on >60% of coding genes, yet interplay between them is little studied. Canonical microRNA binding occurs by base-pairing of microRNA 3′-ends to complementary “seed regions” in mRNA 3′UTRs, resulting in translational repression. Similarly, regulatory RNA-binding proteins bind to mRNAs, modifying stability or translation. We investigated post-transcriptional regulation acting on the xenobiotic pump ABCB1/P-glycoprotein, which is implicated in cancer therapy resistance. We characterised the ABCB1 UTRs in primary breast cancer cells and identified UTR sequences that responded to miR-19b despite lacking a canonical binding site. Sequences did, however, contain consensus sites for the RNA-binding protein HuR. We demonstrated that a tripartite complex of HuR, miR-19b and UTR directs repression of ABCB1/P-glycoprotein expression, with HuR essential for non-canonical miR-19b binding thereby controlling chemosensitivity of breast cancer cells. This exemplifies a new cooperative model between RNA-binding proteins and microRNAs to expand the repertoire of mRNAs that can be regulated. This study suggests a novel therapeutic target to impair P-glycoprotein mediated drug efflux, and also indicates that current microRNA binding predictions that rely on seed regions alone may be too conservative.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 Elsevier B.V. All rights reserved. This is an author produced version of a paper published in Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. Uploaded in accordance with the publisher's self-archiving policy |
Keywords: | breast cancer; post-transcriptional regulation; RNA-binding protein; miRNA; chemo-resistance; P-glycoprotein |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Molecular Gastroenterology (Leeds) |
Funding Information: | Funder Grant number Breast Cancer Research Action Group N/A Leeds Teaching Hospitals Charitable Foundation FUND NUMBER 1T04 British Council, UK Newton Fund Royal Society IE160146 |
Depositing User: | Symplectic Publications |
Date Deposited: | 30 Aug 2018 10:16 |
Last Modified: | 31 Aug 2019 00:41 |
Status: | Published |
Publisher: | Elsevier BV |
Identification Number: | 10.1016/j.bbagrm.2018.08.005 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:134974 |