Metabolic re-programming by MALAT1 depletion in prostate cancer

In this study, we sought to investigate the metabolic role of MALAT1, one of the most abundant cancer-associated long non-coding RNA, in prostate cancer. MALAT1 targeting by gapmerization reduced expression of some tricarboxylic acid cycle enzymes including the malic enzyme 3 and the pyruvate dehydrogenase kinases 1 and 3 as well as the choline kinase A. In consequence, prostate cancer metabolism switched toward a glycolytic phenotype characterized by increased lactate production paralleled by growth arrest, and cell death. Conversely, the function of mitochondrial succinate dehydrogenase and expression of oxphos enzymes was markedly reduced, suggesting for a decreased tricarboxylic acid cycle and mitochondrial respiration activity. Interestingly, a similar effect was observed in several prostate cancer-derived organotypic slice cultures, in which metabolism became more glycolytic and apoptotic. Based on these observations, we elaborated a predictive algorithm, in which those metabolic enzymes sensitive to MALAT1 targeting proven successfully to predict tumor recurrence in a subset of patients. In summary, MALAT1 targeting by gapmerization activates a metabolic switch in the prostate cancer cell and tumor tissue unraveling a role for crucial metabolic enzymes in tumor progression and outcome. Gene expression profiling of prostate cancer cell lines and prostate cancer-derived organotypic slice cultures with MALAT1 targeting by gapmerization reduced expression. For each cell line biological replicate and for each OSC (except for OSC#11 for which low amount of RNA was available), two independent hybridizations were carried out, with dye-swap labelling. PC3 cells with and without Malat1 depletion were hybridized three times, with a technical dye-swap replicate for one of the two independent biological replicates.