Suberoylanilide Hydroxamic Acid (Vorinostat) Up-regulates Progranulin Transcription

Progranulin (GRN) haploinsufficiency is a frequent cause of familial frontotemporal dementia, a currently untreatable progressive neurodegenerative disease. By chemical library screening, we identified suberoylanilide hydroxamic acid (SAHA), a Food and Drug Administration-approved histone deacetylase inhibitor, as an enhancer of GRN expression. SAHA dose-dependently increased GRN mRNA and protein levels in cultured cells and restored near-normal GRN expression in haploinsufficient cells from human subjects. Although elevation of secreted progranulin levels through a post-transcriptional mechanism has recently been reported, this is, to the best of our knowledge, the first report of a small molecule enhancer of progranulin transcription. SAHA has demonstrated therapeutic potential in other neurodegenerative diseases and thus holds promise as a first generation drug for the prevention and treatment of frontotemporal dementia.

[1]  K. Sleegers,et al.  Rescue of Progranulin Deficiency Associated with Frontotemporal Lobar Degeneration by Alkalizing Reagents and Inhibition of Vacuolar ATPase , 2011, The Journal of Neuroscience.

[2]  G. Velmahos,et al.  Treatment with histone deacetylase inhibitor attenuates MAP kinase mediated liver injury in a lethal model of septic shock. , 2010, The Journal of surgical research.

[3]  H. Kirshner.  Frontotemporal Dementia and Primary Progressive Aphasia: An Update , 2010, Current neurology and neuroscience reports.

[4]  R. Tagliaferri,et al.  Discovery of drug mode of action and drug repositioning from transcriptional responses , 2010, Proceedings of the National Academy of Sciences.

[5]  J. Pezzuto,et al.  Pleiotropic mechanisms facilitated by resveratrol and its metabolites. , 2010, The Biochemical journal.

[6]  Kyle V. Butler,et al.  Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A. , 2010, Journal of the American Chemical Society.

[7]  Guiliang Tang,et al.  miR-107 regulates granulin/progranulin with implications for traumatic brain injury and neurodegenerative disease. , 2010, The American journal of pathology.

[8]  F. Zhang,et al.  Anti-inflammatory activities of resveratrol in the brain: role of resveratrol in microglial activation. , 2010, European journal of pharmacology.

[9]  K. Schroder,et al.  Differential effects of selective HDAC inhibitors on macrophage inflammatory responses to the Toll‐like receptor 4 agonist LPS , 2010, Journal of leukocyte biology.

[10]  Robert V Farese,et al.  MicroRNA-29b Regulates the Expression Level of Human Progranulin, a Secreted Glycoprotein Implicated in Frontotemporal Dementia , 2010, PloS one.

[11]  M. Caligiuri,et al.  Sp1/NFkappaB/HDAC/miR-29b regulatory network in KIT-driven myeloid leukemia. , 2010, Cancer cell.

[12]  Li Kai,et al.  Resveratrol enhances p53 acetylation and apoptosis in prostate cancer by inhibiting MTA1/NuRD complex , 2010, International journal of cancer.

[13]  B. Tang.  Resveratrol is neuroprotective because it is not a direct activator of Sirt1—A hypothesis , 2010, Brain Research Bulletin.

[14]  C. Iadecola,et al.  Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice , 2010, The Journal of experimental medicine.

[15]  Venkataraman Thanabal,et al.  SRT1720, SRT2183, SRT1460, and Resveratrol Are Not Direct Activators of SIRT1♦ , 2010, The Journal of Biological Chemistry.

[16]  M. Dragunow,et al.  Pharmacology of epigenetics in brain disorders , 2010, British journal of pharmacology.

[17]  A. Lane,et al.  Histone deacetylase inhibitors in cancer therapy. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  M. Mann,et al.  Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions , 2009, Science.

[19]  Shwu‐Yuan Wu,et al.  Activation of SIRT1 by Resveratrol Represses Transcription of the Gene for the Cytosolic Form of Phosphoenolpyruvate Carboxykinase (GTP) by Deacetylating Hepatic Nuclear Factor 4α* , 2009, The Journal of Biological Chemistry.

[20]  S. Haggarty,et al.  HDAC2 negatively regulates memory formation and synaptic plasticity , 2009, Nature.

[21]  K. Sleegers,et al.  Serum biomarker for progranulin‐associated frontotemporal lobar degeneration , 2009, Annals of neurology.

[22]  R. Petersen,et al.  Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members , 2009, Brain : a journal of neurology.

[23]  P. Davies,et al.  Therapeutic potential of resveratrol in Alzheimer's disease , 2008, BMC Neuroscience.

[24]  L. Thompson,et al.  Therapeutic application of histone deacetylase inhibitors for central nervous system disorders , 2008, Nature Reviews Drug Discovery.

[25]  Peter Heutink,et al.  Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia , 2008, The Lancet Neurology.

[26]  R. Petersen,et al.  Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia , 2008, Human molecular genetics.

[27]  Richard Pazdur,et al.  FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. , 2007, The oncologist.

[28]  I. Mackenzie,et al.  Progranulin: normal function and role in neurodegeneration , 2007, Journal of neurochemistry.

[29]  R. Baron,et al.  Anti‐rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen‐induced arthritis in rodents , 2007, British journal of pharmacology.

[30]  D. Dickson,et al.  Journal of Neuroinflammation BioMed Central Review , 2006 .

[31]  Keith L Black,et al.  Suberoylanilide Hydroxamic Acid, a Histone Deacetylase Inhibitor: Effects on Gene Expression and Growth of Glioma Cells In vitro and In vivo , 2007, Clinical Cancer Research.

[32]  S. Melquist,et al.  Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. , 2006, Human molecular genetics.

[33]  C. Duijn,et al.  Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 , 2006, Nature.

[34]  S. Melquist,et al.  Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 , 2006, Nature.

[35]  Peter Claus,et al.  In vitro and ex vivo evaluation of second‐generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy , 2006, Journal of neurochemistry.

[36]  G. Fantuzzi,et al.  Histone Hyperacetylation Is Associated with Amelioration of Experimental Colitis in Mice1 , 2006, The Journal of Immunology.

[37]  F. Dequiedt,et al.  Subtype selective substrates for histone deacetylases. , 2004, Journal of medicinal chemistry.

[38]  J. Milbrandt,et al.  Increased Nuclear NAD Biosynthesis and SIRT1 Activation Prevent Axonal Degeneration , 2004, Science.

[39]  T. Naoe,et al.  Altered interaction of HDAC5 with GATA-1 during MEL cell differentiation , 2003, Oncogene.

[40]  J. Hodges,et al.  Survival in frontotemporal dementia , 2003, Neurology.

[41]  Stuart L Schreiber,et al.  Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Leslie M Thompson,et al.  Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[43]  A. Bateman,et al.  Structural and functional analysis of a promoter of the human granulin/epithelin gene. , 1996, The Biochemical journal.

[44]  T. Südhof,et al.  Mevinolin, an inhibitor of cholesterol synthesis, induces mRNA for low density lipoprotein receptor in livers of hamsters and rabbits. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Heidemarie Neitzel,et al.  A routine method for the establishment of permanent growing lymphoblastoid cell lines , 1986, Human Genetics.

[46]  M. Haine,et al.  Van Damme A. , 1986 .