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Allele-Specific MicroRNA-Mediated Regulation of a Glycolysis Gatekeeper PDK1 in Cancer Metabolism.

Authors :
Subramaniam S
Jeet V
Gunter JH
Clements JA
Batra J
Source :
Cancers [Cancers (Basel)] 2021 Jul 17; Vol. 13 (14). Date of Electronic Publication: 2021 Jul 17.
Publication Year :
2021

Abstract

Background: Emerging evidence has revealed that genetic variations in microRNA (miRNA) binding sites called miRSNPs can alter miRNA binding in an allele-specific manner and impart prostate cancer (PCa) risk. Two miRSNPs, rs1530865 (G > C) and rs2357637 (C > A), in the 3' untranslated region of pyruvate dehydrogenase kinase 1 (PDK1) have been previously reported to be associated with PCa risk. However, these results have not been functionally validated.<br />Methods: In silico analysis was used to predict miRNA-PDK1 interactions and was tested using PDK1 knockdown, miRNA overexpression and reporter gene assay.<br />Results: PDK1 expression was found to be upregulated in PCa metastasis. Further, our results show that PDK1 suppression reduced the migration, invasion, and glycolysis of PCa cells. Computational predictions showed that miR-3916, miR-3125 and miR-3928 had a higher binding affinity for the C allele than the G allele for the rs1530865 miRSNP which was validated by reporter gene assays. Similarly, miR-2116 and miR-889 had a higher affinity for the A than C allele of the rs2357637 miRSNP. Overexpression of miR-3916 and miR-3125 decreased PDK1 protein levels in cells expressing the rs1530865 SNP C allele, and miR-2116 reduced in cells with the rs2357637 SNP A allele.<br />Conclusions: The present study is the first to report the regulation of the PDK1 gene by miRNAs in an allele-dependent manner and highlights the role of PDK1 in metabolic adaption associated with PCa progression.

Details

Language :
English
ISSN :
2072-6694
Volume :
13
Issue :
14
Database :
MEDLINE
Journal :
Cancers
Publication Type :
Academic Journal
Accession number :
34298795
Full Text :
https://doi.org/10.3390/cancers13143582