Fragiadaki, M. and Zeidler, M.P. (2018) Ankyrin repeat and Single KH domain 1 (ANKHD1) drives renal cancer cell proliferation via binding to and altering a subset of miRNAs. Journal of Biological Chemistry , 293. pp. 9570-9579. ISSN 0021-9258
Abstract
Clear cell Renal Cell Carcinoma (ccRCC) represents the most common kidney cancer worldwide. Increased cell proliferation associated with abnormal microRNA (miRNA) regulation are hallmarks of carcinogenesis. Ankyrin repeat and single KH domain 1 (ANKHD1) is a highly conserved protein found to interact with core cancer pathways in Drosophila, however its involvement in RCC is completely unexplored. Quantitative PCR studies coupled with large-scale genomics data analyses demonstrated that ANKHD1 is significantly upregulated in kidneys of RCC patients when compared to healthy controls. Cell cycle analyses revealed that ANKHD1 is an essential factor for RCC cell division. To understand the molecular mechanism(s) utilized by ANKHD1 to drive RCC cell proliferation we performed bioinformatics analyses which revealed that ANKHD1 contains a putative miRNA-binding motif. We screened 48 miRNAs with tumour-enhancing or suppressing activities, and found that ANKHD1 binds to and regulates three tumour-suppressing miRNAs (i.e. miR-29a, miR-205, and miR-196a). RNA-immunoprecipitation assays demonstrated that ANKHD1 physically interacts with its target miRNAs via a single K-Homology (KH)-domain, located in the c-terminus of the protein. Functionally we discovered that ANKHD1 positively drives ccRCC cell mitosis via binding to and suppressing mainly miR-29a and to a lesser degree via miR-196a/205, leading to an upregulation in pro-proliferative genes such as CCDN1. Collectively, these data identify ANKHD1 as a new regulator of ccRCC proliferation via specific miRNA interactions.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 by The American Society for Biochemistry and Molecular Biology, Inc. Reproduced in accordance with the publisher's self-archiving policy. |
Keywords: | ANKHD1; cancer biology; ccRCC; cell proliferation; clear cell; kidney; miR-29a; miRNA-binding; microRNA (miRNA); microRNA mechanism |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Biomedical Science (Sheffield) |
Funding Information: | Funder Grant number KIDNEY RESEARCH UK PDF7/2015 University of Sheffield Thomas-Berry and Simpson Fellowship University of Sheffield Women Academic Returners' program (WARP) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 01 May 2018 15:16 |
Last Modified: | 21 Nov 2020 09:51 |
Status: | Published |
Publisher: | American Society for Biochemistry and Molecular Biology |
Refereed: | Yes |
Identification Number: | 10.1074/jbc.RA117.000975 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:130240 |