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.
Highlights
The disruption of normal gene regulation due to microRNA dysfunction is a common event in cancer pathogenesis
A cut-off was set for each program giving a binary prediction indicated as 1 or 0
MicroRNA-27b targets the 3’UTR of PDHX There are multiple miRNA target prediction programs available for identifying putative targets of a miRNA of interest, each providing comparable but non-identical predictions depending on how the various parameters are weighted
Summary
The disruption of normal gene regulation due to microRNA dysfunction is a common event in cancer pathogenesis. The past two decades have spawned a transformation in the understanding of gene expression and its regulation This shift has been largely driven by the growing awareness of the profound role that noncoding gene products perform within cells, microRNA (miRNA), which is a class of short (18-25 nt) regulatory RNAs first discovered in 1993 [1, 2]. Given their widespread involvement in control of gene expression, dysfunction of normal miRNA regulation has emerged as an important mechanism in disease, especially cancer. One such example is miRNA-27b, which primarily functions as an oncogenic miRNA (oncomir) in breast cancer (BC) by targeting multiple. MiR-27b appears to perform a multi-faceted role in cancer promotion, regulating multiple different oncogenic processes
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