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Simple Summary: Prostate cancer (PCa) is one of the most common cancers in developed countries, being the second leading cause of cancer death among men. Surgery is the primary therapeutic option, but about one-third of patients develop a recurrence within ten years, for which successful therapy is unavailable. Based on these observations, it has become urgent to develop novel molecular tools for predicting clinical outcome. Here, we focus on one of the best characterized cancer-associated long non-coding transcripts, namely metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). This study highlighted a novel role for MALAT1 as a controller of prostate cancer metabolism. MALAT1 silencing caused a metabolic rewire in both experimental models adopted, prostate cancer cell lines, and organotypic slice cultures derived from surgical specimens. PCa cells upon MALAT1 silencing revert their phenotype towards glycolysis, which is characteristic of normal prostate cells. In this regard, MALAT1 targeting may represent a promising diagnostic tool and a novel therapeutic option. The lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes growth and progression in prostate cancer (PCa); however, little is known about its possible impact in PCa metabolism. The aim of this work has been the assessment of the metabolic reprogramming associated with MALAT1 silencing in human PCa cells and in an ex vivo model of organotypic slice cultures (OSCs). Cultured cells and OSCs derived from primary tumors were transfected with MALAT1 specific gapmers. Cell growth and survival, gene profiling, and evaluation of targeted metabolites and metabolic enzymes were assessed. Computational analysis was made considering expression changes occurring in metabolic markers following MALAT1 targeting in cultured OSCs. MALAT1 silencing reduced expression of some metabolic enzymes, including malic enzyme 3, pyruvate dehydrogenase kinases 1 and 3, and choline kinase A. Consequently, PCa 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 the expression of oxidative phosphorylation enzymes were markedly reduced. A similar effect was observed in OSCs. Based on this, a predictive algorithm was developed aimed to predict tumor recurrence in a subset of patients. MALAT1 targeting by gapmer delivery restored normal metabolic energy pathway in PCa cells and OSCs. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is a genetic disease associated with mutations of Dystrophin gene that regulate myofiber integrity and muscle degeneration, characterized by oxidative stress increase. We previously published that reactive oxygen species (ROS) induce miR-200c that is responsible for apoptosis and senescence. Moreover, we demonstrated that miR-200c increases ROS production and phosphorylates p66Shc in Ser-36. p66Shc plays an important role in muscle differentiation; we previously showed that p66Shc -/- muscle satellite cells display lower oxidative stress levels and higher proliferation rate and differentiated faster than wild-type ( wt ) cells. Moreover, myogenic conversion, induced by MyoD overexpression, is more efficient in p66Shc -/- fibroblasts compared to wt cells. Herein, we report that miR-200c overexpression in cultured myoblasts impairs skeletal muscle differentiation. Further, its overexpression in differentiated myotubes decreases differentiation indexes. Moreover, anti-miR-200c treatment ameliorates myogenic differentiation. In keeping, we found that miR-200c and p66Shc Ser-36 phosphorylation increase in mdx muscles. In conclusion, miR-200c inhibits muscle differentiation, whereas its inhibition ameliorates differentiation and its expression levels are increased in mdx mice and in differentiated human myoblasts of DMD. Therefore, miR-200c might be responsible for muscle wasting and myotube loss, most probably via a p66Shc-dependent mechanism in a pathological disease such as DMD.