Quantitative Analysis of the Proteome Response to the Histone Deacetylase Inhibitor (HDACi) Vorinostat in Niemann-Pick Type C1 disease

• Published in: Molecular & cellular proteomics 2017-11, Vol.16 (11), p.1938-1957
• Main Authors: Subramanian, Kanagaraj, Rauniyar, Navin, Lavalleé-Adam, Mathieu, Yates, John R., Balch, William E.
• Format: Article
• Language: English
• Subjects: Acetylation; Cell Line; Cholesterol; Chromatin; Deacetylation; Endosomes; Energy Metabolism; Epigenetics; Fibroblasts; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Folding; Gene Expression Regulation - drug effects; HeLa Cells; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Homeostasis; Humans; Hydroxamic Acids - pharmacology; Inhibitors; LipA protein; Lipase; Lipid Metabolism; Lysosomes; Mass Spectrometry; Metabolism; Mitigation; Mutation; Neurodegenerative diseases; Niemann-Pick disease; Niemann-Pick Disease, Type C - metabolism; Npc1 protein; Post-translation; Protein folding; Protein transport; Protein turnover; Proteins; Proteome - drug effects; Proteomics - methods; Quantitative analysis; Vorinostat
• ISSN: 1535-9476; 1535-9484
• DOI: 10.1074/mcp.M116.064949

Niemann-Pick type C (NPC) disease is an inherited, progressive neurodegenerative disorder principally caused by mutations in the NPC1 gene. NPC disease is characterized by the accumulation of unesterified cholesterol in the late endosomes (LE) and lysosomes (Ly) (LE/Ly). Vorinostat, a histone deacetylase inhibitor (HDACi), restores cholesterol homeostasis in fibroblasts derived from NPC patients; however, the exact mechanism by which Vorinostat restores cholesterol level is not known yet. In this study, we performed comparative proteomic profiling of the response of NPC1I1061T fibroblasts to Vorinostat. After stringent statistical criteria to filter identified proteins, we observed 202 proteins that are differentially expressed in Vorinostat-treated fibroblasts. These proteins are members of diverse cellular pathways including the endomembrane dependent protein folding-stability-degradation-trafficking axis, energy metabolism, and lipid metabolism. Our study shows that treatment of NPC1I1061T fibroblasts with Vorinostat not only enhances pathways promoting the folding, stabilization and trafficking of NPC1 (I1061T) mutant to the LE/Ly, but alters the expression of lysosomal proteins, specifically the lysosomal acid lipase (LIPA) involved in the LIPA->NPC2->NPC1 based flow of cholesterol from the LE/Ly lumen to the LE/Ly membrane. We posit that the Vorinostat may modulate numerous pathways that operate in an integrated fashion through epigenetic and post-translational modifications reflecting acetylation/deacetylation balance to help manage the defective NPC1 fold, the function of the LE/Ly system and/or additional cholesterol metabolism/distribution pathways, that could globally contribute to improved mitigation of NPC1 disease in the clinic based on as yet uncharacterized principles of cellular metabolism dictating cholesterol homeostasis.