Prostate cancer (PCa) cells are known to heavily depend on lipids to support their growth. We hypothesized that hyperlipidemic factors, for which inhibitors are already available and used to treat car Show more
Prostate cancer (PCa) cells are known to heavily depend on lipids to support their growth. We hypothesized that hyperlipidemic factors, for which inhibitors are already available and used to treat cardiovascular disease, would be dysregulated in metastatic PCa (mPCa). The goal of this case-control study, including 35 men per group, was to compare the levels of PCSK9, ANGPTL3, Apo CIII, leptin, and the lipid profile in patients with mPCa versus localized Gleason 8/9 PCa (lPCa) and patients at risk of developing PCa (controls). Protein levels were assessed using ELISAs, while lipids were measured using the Roche Cobas analytical platform. The following circulating analytes were higher in mPCa: triglycerides (in mmol/L; controls 1.7 ± 1.2, lPCa 1.5 ± 0.7, mPCa 2.3 ± 1.2, In this cohort of men, whole-body lipid metabolic rewiring is a feature restricted to the metastatic phase of prostate cancer, suggesting it may play a significant role in the progression toward more aggressive cancer forms. Given the availability of drugs targeting ANGPTL3 and Apo CIII, the therapeutic potential of these drugs should be evaluated in metastatic PCa. Show less
MEF2 plays a profound role in the regulation of transcription in cardiac and skeletal muscle lineages. To define the overlapping and unique MEF2A genomic targets, we utilized ChIP-exo analysis of card Show more
MEF2 plays a profound role in the regulation of transcription in cardiac and skeletal muscle lineages. To define the overlapping and unique MEF2A genomic targets, we utilized ChIP-exo analysis of cardiomyocytes and skeletal myoblasts. Of the 2783 and 1648 MEF2A binding peaks in skeletal myoblasts and cardiomyocytes, respectively, 294 common binding sites were identified. Genomic targets were compared to differentially expressed genes in RNA-seq analysis of MEF2A depleted myogenic cells, revealing two prominent genetic networks. Genes largely associated with muscle development were down-regulated by loss of MEF2A while up-regulated genes reveal a previously unrecognized function of MEF2A in suppressing growth/proliferative genes. Several up-regulated (Tprg, Mctp2, Kitl, Prrx1, Dusp6) and down-regulated (Atp1a2, Hspb7, Tmem182, Sorbs2, Lmod3) MEF2A target genes were chosen for further investigation. Interestingly, siRNA targeting of the MEF2A/D heterodimer revealed a somewhat divergent role in the regulation of Dusp6, a MAPK phosphatase, in cardiac and skeletal myogenic lineages. Furthermore, MEF2D functions as a p38MAPK-dependent repressor of Dusp6 in myoblasts. These data illustrate that MEF2 orchestrates both common and non-overlapping programs of signal-dependent gene expression in skeletal and cardiac muscle lineages. Show less