👤 Maria Barile

Lysine-specific demethylase 1 (LSD1) is a key regulator in cancer epigenetic, and its activity is reliant on flavin adenine dinucleotide (FAD) as a cofactor. In this study, we investigated the correlation between LSD1 and FAD synthase isoform 2 (FADS2) protein levels in pancreatic ductal adenocarcinoma (PDAC) cell lines. We first assessed LSD1 protein and mRNA levels in mutant p53-expressing PANC-1 and MiaPaCa2 cells and p53-null AsPc-1 cells, compared to human pancreatic ductal epithelial (HPDE) controls. Our results confirmed elevated LSD1 protein levels in PANC-1 and MiaPaCa2, but not in AsPc-1, despite mRNA overexpression across all cell lines. Similarly, FADS2 levels were significantly upregulated in PANC-1 and MiaPaCa2, but not in AsPc-1, highlighting a possible link between FADS2 expression and p53 gain-of-function mutations. These results prompted us to better investigate the functional relationship between FADS2 and LSD1 by performing in cellulo protein-protein interaction analyses. Our results indicate a direct interaction between LSD1 and FADS2, while no significant interaction was observed between LSD1 and FADS1. These findings reinforce the role of FAD synthesis and its delivery to LSD1 as critical events in cancer progression and shed light on potential implications of FADS2-LSD1 dynamics as targeted therapies in cancer. Show less

Advanced age-related macular degeneration (AMD) is the leading cause of late onset blindness. We present results of a genome-wide association study of 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in seven additional cohorts (totaling 5,789 unrelated cases and 4,234 unrelated controls). We also present a comprehensive analysis of copy-number variations and polymorphisms for AMD. Our discovery data implicated the association between AMD and a variant in the hepatic lipase gene (LIPC) in the high-density lipoprotein cholesterol (HDL) pathway (discovery P = 4.53e-05 for rs493258). Our LIPC association was strongest for a functional promoter variant, rs10468017, (P = 1.34e-08), that influences LIPC expression and serum HDL levels with a protective effect of the minor T allele (HDL increasing) for advanced wet and dry AMD. The association we found with LIPC was corroborated by the Michigan/Penn/Mayo genome-wide association study; the locus near the tissue inhibitor of metalloproteinase 3 was corroborated by our replication cohort for rs9621532 with P = 3.71e-09. We observed weaker associations with other HDL loci (ABCA1, P = 9.73e-04; cholesterylester transfer protein, P = 1.41e-03; FADS1-3, P = 2.69e-02). Based on a lack of consistent association between HDL increasing alleles and AMD risk, the LIPC association may not be the result of an effect on HDL levels, but it could represent a pleiotropic effect of the same functional component. Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD. Show less