Allele-Specific MicroRNA-Mediated Regulation of a Glycolysis Gatekeeper PDK1 in Cancer Metabolism
| Autor: | Sugarniya Subramaniam, Jyotsna Batra, Jennifer H. Gunter, Varinder Jeet, Judith A. Clements |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Reporter gene Gene knockdown Pyruvate dehydrogenase kinase animal structures Neoplasms. Tumors. Oncology. Including cancer and carcinogens Single-nucleotide polymorphism MiRNA binding Biology Molecular biology Article microRNAs 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology PDK1 030220 oncology & carcinogenesis microRNA single-nucleotide polymorphisms metabolic reprogramming Allele Gene RC254-282 |
| Zdroj: | Cancers Volume 13 Issue 14 Cancers, Vol 13, Iss 3582, p 3582 (2021) |
| ISSN: | 2072-6694 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|