Allele-Specific MicroRNA-Mediated Regulation of a Glycolysis Gatekeeper PDK1 in Cancer Metabolism
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...
Main Authors: | , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2021-07-01
|
Series: | Cancers |
Subjects: | |
Online Access: | https://www.mdpi.com/2072-6694/13/14/3582 |
id |
doaj-02ac2e23d16d43cca386805287452217 |
---|---|
record_format |
Article |
spelling |
doaj-02ac2e23d16d43cca3868052874522172021-07-23T13:33:50ZengMDPI AGCancers2072-66942021-07-01133582358210.3390/cancers13143582Allele-Specific MicroRNA-Mediated Regulation of a Glycolysis Gatekeeper PDK1 in Cancer MetabolismSugarniya Subramaniam0Varinder Jeet1Jennifer H. Gunter2Judith A. Clements3Jyotsna Batra4School of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane 4000, AustraliaSchool of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane 4000, AustraliaSchool of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane 4000, AustraliaSchool of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane 4000, AustraliaSchool of Biomedical Sciences, Faculty of Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane 4000, AustraliaBackground: 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. Methods: In silico analysis was used to predict miRNA–PDK1 interactions and was tested using PDK1 knockdown, miRNA overexpression and reporter gene assay. 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. 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.https://www.mdpi.com/2072-6694/13/14/3582PDK1metabolic reprogrammingsingle-nucleotide polymorphismsmicroRNAs |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sugarniya Subramaniam Varinder Jeet Jennifer H. Gunter Judith A. Clements Jyotsna Batra |
spellingShingle |
Sugarniya Subramaniam Varinder Jeet Jennifer H. Gunter Judith A. Clements Jyotsna Batra Allele-Specific MicroRNA-Mediated Regulation of a Glycolysis Gatekeeper PDK1 in Cancer Metabolism Cancers PDK1 metabolic reprogramming single-nucleotide polymorphisms microRNAs |
author_facet |
Sugarniya Subramaniam Varinder Jeet Jennifer H. Gunter Judith A. Clements Jyotsna Batra |
author_sort |
Sugarniya Subramaniam |
title |
Allele-Specific MicroRNA-Mediated Regulation of a Glycolysis Gatekeeper PDK1 in Cancer Metabolism |
title_short |
Allele-Specific MicroRNA-Mediated Regulation of a Glycolysis Gatekeeper PDK1 in Cancer Metabolism |
title_full |
Allele-Specific MicroRNA-Mediated Regulation of a Glycolysis Gatekeeper PDK1 in Cancer Metabolism |
title_fullStr |
Allele-Specific MicroRNA-Mediated Regulation of a Glycolysis Gatekeeper PDK1 in Cancer Metabolism |
title_full_unstemmed |
Allele-Specific MicroRNA-Mediated Regulation of a Glycolysis Gatekeeper PDK1 in Cancer Metabolism |
title_sort |
allele-specific microrna-mediated regulation of a glycolysis gatekeeper pdk1 in cancer metabolism |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2021-07-01 |
description |
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. Methods: In silico analysis was used to predict miRNA–PDK1 interactions and was tested using PDK1 knockdown, miRNA overexpression and reporter gene assay. 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. 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. |
topic |
PDK1 metabolic reprogramming single-nucleotide polymorphisms microRNAs |
url |
https://www.mdpi.com/2072-6694/13/14/3582 |
work_keys_str_mv |
AT sugarniyasubramaniam allelespecificmicrornamediatedregulationofaglycolysisgatekeeperpdk1incancermetabolism AT varinderjeet allelespecificmicrornamediatedregulationofaglycolysisgatekeeperpdk1incancermetabolism AT jenniferhgunter allelespecificmicrornamediatedregulationofaglycolysisgatekeeperpdk1incancermetabolism AT judithaclements allelespecificmicrornamediatedregulationofaglycolysisgatekeeperpdk1incancermetabolism AT jyotsnabatra allelespecificmicrornamediatedregulationofaglycolysisgatekeeperpdk1incancermetabolism |
_version_ |
1721289062848921600 |