Suppression of PDHX by microRNA-27b deregulates cell metabolism and promotes growth in breast cancer

Abstract

BackgroundThe 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.MethodsWe 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.ResultsOur 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.ConclusionsMicroRNA-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.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0851-8) contains supplementary material, which is available to authorized users.

SIRT3 elicited an anti‐Warburg effect through HIF1α/PDK1/PDHA1 to inhibit cholangiocarcinoma tumorigenesis

“…Phosphorylation‐dependent inhibition of PDH is a related event in this process. PDH plays a crucial regulatory role by tuning glycolytic metabolism in cancer cells . Enhanced glycolysis inhibited pyruvate dehydrogenase flow, and downregulated TCA cycle labeling, consistent with the Warburg effect .…”

miR-26a is Involved in Glycometabolism and Affects Boar Sperm Viability by Targeting PDHX

“…Since then, numerous studies have demonstrated that the occurrence of mutations in PDHX gene are due to PDH deficiency [24][25][26]. In addition, PDHX is inhibited by miR-27b and regulates the metabolic proliferation of breast cancer cells, which leads to reduced patient survival [27].…”

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“…This function was supported by anti-type II diabetes (T2D) drug metformin, that counteracted the generation of CSCs [189]. MiR-27b was also shown to promote the Warburg effect, by inhibiting the PDHX with subsequent dysregulation of the levels of pyruvate, lactate and citrate that increase cell proliferation in the Luminal A and TNBC subtypes [190].…”