Targeting PDK4 inhibits breast cancer metabolism

Dysregulated metabolism in the form of aerobic glycolysis occurs in many cancers including breast carcinoma. Here, we report PDK4 (pyruvate dehydrogenase kinase 4) as key enzyme implicated in the control of glucose metabolism and mitochondrial respiration is relatively highly expressed in breast cancers, and its expression correlates with poor patient outcomes. Silencing of PDK4 and ectopic expression of miR-211 attenuates PDK4 expression in breast cancer cells. Interestingly, low miR-211 expression is significantly associated with shorter overall survival and reveals an inverse correlation between expression of miR-211 and PDK4. We have found that depletion of PDK4 by miR-211 shows an oxidative phosphorylation-dominant phenotype consisting of the reduction of glucose with increased expression of PDH and key enzymes of the TCA cycle. miR-211 expression causes alteration of mitochondrial membrane potential and induces mitochondrial apoptosis as observed via IPAD assay. Further, by inhibiting PDK4 expression, miR-211 promotes a phenotype shift towards a pro-glycolytic state evidenced by decreased extracellular acidification rate (ECAR); increased oxygen consumption rate (OCR); and increased spare respiratory capacity in breast cancer cell lines. Taken together this data establishes a molecular connection between PDK4 and miR-211 and suggests that targeting miR-211 to inhibit PDK4 could represent a novel therapeutic strategy in breast cancers.