Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancer
Abstract Background The disruption of normal gene regulation due to microRNA dysfunction is a common event in cancer pathogenesis. MicroRNA-27b is an example of an oncogenic miRNA, and it is frequently upregulated in breast cancer. MicroRNAs have been found to deregulate tumor metabolism, which typi...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-07-01
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| Series: | Molecular Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12943-018-0851-8 |
| _version_ | 1811270541795917824 |
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| author | Steven C. Eastlack Shengli Dong Cristina Ivan Suresh K. Alahari |
| author_facet | Steven C. Eastlack Shengli Dong Cristina Ivan Suresh K. Alahari |
| author_sort | Steven C. Eastlack |
| collection | DOAJ |
| description | Abstract Background The disruption of normal gene regulation due to microRNA dysfunction is a common event in cancer pathogenesis. MicroRNA-27b is an example of an oncogenic miRNA, and it is frequently upregulated in breast cancer. MicroRNAs have been found to deregulate tumor metabolism, which typically manifests as heightened cellular glucose uptake in consort with increased flux through glycolysis, followed by the preferential conversion of glycolytic pyruvate into lactate (a phenomenon known as the Warburg Effect). Pyruvate Dehydrogenase, an enzyme complex linking glycolysis with downstream oxidative metabolism, represents a key location where regulation of metabolism occurs; PDHX is a key structural component of this complex and is essential for its function. Methods We sought to characterize the role of miR-27b in breast cancer by identifying novel transcripts under its control. We began by utilizing luciferase, RNA, and protein assays to establish PDHX as a novel target of miR-27b. We then tested whether miR-27b could alter metabolism using several metabolite assay kits and performed a seahorse analysis. We also examined how the altered metabolism might affect cell proliferation. Lastly, we confirmed the relevance of our findings in human breast tumor samples. Results Our data indicate that Pyruvate Dehydrogenase Protein X is a credible target of miR-27b in breast cancer. Mechanistically, by suppressing PDHX, miR-27b altered levels of pyruvate, lactate and citrate, as well as reducing mitochondrial oxidation and promoting extracellular acidification. These changes corresponded with an increased capacity for cell proliferation. In human breast tumor samples, PDHX expression was deficient, and low levels of PDHX were associated with reduced patient survival. Conclusions MicroRNA-27b targets PDHX, resulting in an altered metabolic configuration that is better suited to fuel biosynthetic processes and cell proliferation, thereby promoting breast cancer progression. |
| first_indexed | 2024-04-12T22:02:38Z |
| format | Article |
| id | doaj.art-326a716502c74f5e853a8e3d4b83dba5 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-04-12T22:02:38Z |
| publishDate | 2018-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-326a716502c74f5e853a8e3d4b83dba52022-12-22T03:15:02ZengBMCMolecular Cancer1476-45982018-07-0117111610.1186/s12943-018-0851-8Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancerSteven C. Eastlack0Shengli Dong1Cristina Ivan2Suresh K. Alahari3Department of Biochemistry and Molecular Biology, Stanley S. Scott Cancer Center, LSUHSC School of MedicineDepartment of Biochemistry and Molecular Biology, Stanley S. Scott Cancer Center, LSUHSC School of MedicineDepartment of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer CenterDepartment of Biochemistry and Molecular Biology, Stanley S. Scott Cancer Center, LSUHSC School of MedicineAbstract Background The disruption of normal gene regulation due to microRNA dysfunction is a common event in cancer pathogenesis. MicroRNA-27b is an example of an oncogenic miRNA, and it is frequently upregulated in breast cancer. MicroRNAs have been found to deregulate tumor metabolism, which typically manifests as heightened cellular glucose uptake in consort with increased flux through glycolysis, followed by the preferential conversion of glycolytic pyruvate into lactate (a phenomenon known as the Warburg Effect). Pyruvate Dehydrogenase, an enzyme complex linking glycolysis with downstream oxidative metabolism, represents a key location where regulation of metabolism occurs; PDHX is a key structural component of this complex and is essential for its function. Methods We sought to characterize the role of miR-27b in breast cancer by identifying novel transcripts under its control. We began by utilizing luciferase, RNA, and protein assays to establish PDHX as a novel target of miR-27b. We then tested whether miR-27b could alter metabolism using several metabolite assay kits and performed a seahorse analysis. We also examined how the altered metabolism might affect cell proliferation. Lastly, we confirmed the relevance of our findings in human breast tumor samples. Results Our data indicate that Pyruvate Dehydrogenase Protein X is a credible target of miR-27b in breast cancer. Mechanistically, by suppressing PDHX, miR-27b altered levels of pyruvate, lactate and citrate, as well as reducing mitochondrial oxidation and promoting extracellular acidification. These changes corresponded with an increased capacity for cell proliferation. In human breast tumor samples, PDHX expression was deficient, and low levels of PDHX were associated with reduced patient survival. Conclusions MicroRNA-27b targets PDHX, resulting in an altered metabolic configuration that is better suited to fuel biosynthetic processes and cell proliferation, thereby promoting breast cancer progression.http://link.springer.com/article/10.1186/s12943-018-0851-8Breast cancerMetabolismWarburg effectmicroRNALactatePyruvate dehydrogenase |
| spellingShingle | Steven C. Eastlack Shengli Dong Cristina Ivan Suresh K. Alahari Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancer Molecular Cancer Breast cancer Metabolism Warburg effect microRNA Lactate Pyruvate dehydrogenase |
| title | Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancer |
| title_full | Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancer |
| title_fullStr | Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancer |
| title_full_unstemmed | Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancer |
| title_short | Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancer |
| title_sort | suppression of pdhx by microrna 27b deregulates cell metabolism and promotes growth in breast cancer |
| topic | Breast cancer Metabolism Warburg effect microRNA Lactate Pyruvate dehydrogenase |
| url | http://link.springer.com/article/10.1186/s12943-018-0851-8 |
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