MS-275 inhibits aroclor 1254-induced SH-SY5Y neuronal cell toxicity by preventing the formation of the HDAC3/REST complex on the synapsin-1 promoter

Luigi Formisano, Natascia Guida, Guisy Laudati, Luigi Mascolo, Gianfranco Di Renzo, Lorella M T Canzoniero

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Polychlorinated biphenyl (PCB) exposure has been associated with neurodegenerative diseases, such as Parkinson's disease, amyotrophic lateral sclerosis, and dementia. Neuronal death elicited by the PCB mixture Aroclor 1254 (A1254) has been attributed to an increase in RE-1-silencing transcription factor (REST), which, in turn, correlates with a decrease in the synapsin-1 promoter gene. Although histone deacetylase (HDAC) inhibitors are known to be neuroprotective in several neurologic disorders, the coremechanisms governing this effect are not yet understood. Here, to examine how HDAC class I [N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)aminomethyl]-benzamide (MS-275)] and HDAC class II [3-[5-(3-(3-fluorophenyl)-3-oxopropen-1-yl)-1-methyl-1H-pyrrol-2-yl]-N-hydroxy-2-propenamide (MC-1568)] inhibitors prevent A1254-induced neuronal cell death, we exposed SH-SY5Y neuroblastoma cells to A1254. Exposure to A1254 (30.6 μM) for 24 and 48 hours resulted in a time-dependent cell death. Indeed, after 48 hours, MS-275, but not MC-1568, reverted A1254-induced cell death in a dose-dependent manner. Furthermore, A1254 significantly increased HDAC3, but not HDAC1 or HDAC2. Interestingly, REST physically interacted with HDAC3 after A1254 exposure. Chromatin immunoprecipitation assays revealed that MS-275 reverted the increased levels of HDAC3 binding and decreased acetylation of histone H3 within the synapsin-1 promoter region, thus reverting synapsin-1 mRNA reduction. Moreover, REST knockdown by small interfering RNA (siRNA) prevented HDAC3 from binding to the synapsin-1 promoter. Likewise, HDAC3 siRNA significantly reduced A1254-induced cell toxicity in SH-SY5Y cells and cortical neurons. Hence, this study demonstrates that inhibition of HDAC class I attenuates A1254-induced neuronal cell death by preventing HDAC3 binding and histone deacetylation within the synapsin-1 promoter region.

Original languageEnglish
Article numberA6
Pages (from-to)236-243
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume352
Issue number2
DOIs
Publication statusPublished - Jan 1 2015

Fingerprint

Chlorodiphenyl (54% Chlorine)
Synapsins
Transcription Factors
Histone Deacetylases
Cell Death
Polychlorinated Biphenyls
Genetic Promoter Regions
Histones
Small Interfering RNA
entinostat
Histone Deacetylase Inhibitors
Chromatin Immunoprecipitation
Amyotrophic Lateral Sclerosis
Acetylation
Nervous System Diseases
Neuroblastoma
Neurodegenerative Diseases
Parkinson Disease
Dementia
Neurons

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Medicine(all)

Cite this

MS-275 inhibits aroclor 1254-induced SH-SY5Y neuronal cell toxicity by preventing the formation of the HDAC3/REST complex on the synapsin-1 promoter. / Formisano, Luigi; Guida, Natascia; Laudati, Guisy; Mascolo, Luigi; Di Renzo, Gianfranco; Canzoniero, Lorella M T.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 352, No. 2, A6, 01.01.2015, p. 236-243.

Research output: Contribution to journalArticle

Formisano, Luigi ; Guida, Natascia ; Laudati, Guisy ; Mascolo, Luigi ; Di Renzo, Gianfranco ; Canzoniero, Lorella M T. / MS-275 inhibits aroclor 1254-induced SH-SY5Y neuronal cell toxicity by preventing the formation of the HDAC3/REST complex on the synapsin-1 promoter. In: Journal of Pharmacology and Experimental Therapeutics. 2015 ; Vol. 352, No. 2. pp. 236-243.
@article{e51c14602e284d1fa66393d90cc35312,
title = "MS-275 inhibits aroclor 1254-induced SH-SY5Y neuronal cell toxicity by preventing the formation of the HDAC3/REST complex on the synapsin-1 promoter",
abstract = "Polychlorinated biphenyl (PCB) exposure has been associated with neurodegenerative diseases, such as Parkinson's disease, amyotrophic lateral sclerosis, and dementia. Neuronal death elicited by the PCB mixture Aroclor 1254 (A1254) has been attributed to an increase in RE-1-silencing transcription factor (REST), which, in turn, correlates with a decrease in the synapsin-1 promoter gene. Although histone deacetylase (HDAC) inhibitors are known to be neuroprotective in several neurologic disorders, the coremechanisms governing this effect are not yet understood. Here, to examine how HDAC class I [N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)aminomethyl]-benzamide (MS-275)] and HDAC class II [3-[5-(3-(3-fluorophenyl)-3-oxopropen-1-yl)-1-methyl-1H-pyrrol-2-yl]-N-hydroxy-2-propenamide (MC-1568)] inhibitors prevent A1254-induced neuronal cell death, we exposed SH-SY5Y neuroblastoma cells to A1254. Exposure to A1254 (30.6 μM) for 24 and 48 hours resulted in a time-dependent cell death. Indeed, after 48 hours, MS-275, but not MC-1568, reverted A1254-induced cell death in a dose-dependent manner. Furthermore, A1254 significantly increased HDAC3, but not HDAC1 or HDAC2. Interestingly, REST physically interacted with HDAC3 after A1254 exposure. Chromatin immunoprecipitation assays revealed that MS-275 reverted the increased levels of HDAC3 binding and decreased acetylation of histone H3 within the synapsin-1 promoter region, thus reverting synapsin-1 mRNA reduction. Moreover, REST knockdown by small interfering RNA (siRNA) prevented HDAC3 from binding to the synapsin-1 promoter. Likewise, HDAC3 siRNA significantly reduced A1254-induced cell toxicity in SH-SY5Y cells and cortical neurons. Hence, this study demonstrates that inhibition of HDAC class I attenuates A1254-induced neuronal cell death by preventing HDAC3 binding and histone deacetylation within the synapsin-1 promoter region.",
author = "Luigi Formisano and Natascia Guida and Guisy Laudati and Luigi Mascolo and {Di Renzo}, Gianfranco and Canzoniero, {Lorella M T}",
year = "2015",
month = "1",
day = "1",
doi = "10.1124/jpet.114.219345",
language = "English",
volume = "352",
pages = "236--243",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - MS-275 inhibits aroclor 1254-induced SH-SY5Y neuronal cell toxicity by preventing the formation of the HDAC3/REST complex on the synapsin-1 promoter

AU - Formisano, Luigi

AU - Guida, Natascia

AU - Laudati, Guisy

AU - Mascolo, Luigi

AU - Di Renzo, Gianfranco

AU - Canzoniero, Lorella M T

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Polychlorinated biphenyl (PCB) exposure has been associated with neurodegenerative diseases, such as Parkinson's disease, amyotrophic lateral sclerosis, and dementia. Neuronal death elicited by the PCB mixture Aroclor 1254 (A1254) has been attributed to an increase in RE-1-silencing transcription factor (REST), which, in turn, correlates with a decrease in the synapsin-1 promoter gene. Although histone deacetylase (HDAC) inhibitors are known to be neuroprotective in several neurologic disorders, the coremechanisms governing this effect are not yet understood. Here, to examine how HDAC class I [N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)aminomethyl]-benzamide (MS-275)] and HDAC class II [3-[5-(3-(3-fluorophenyl)-3-oxopropen-1-yl)-1-methyl-1H-pyrrol-2-yl]-N-hydroxy-2-propenamide (MC-1568)] inhibitors prevent A1254-induced neuronal cell death, we exposed SH-SY5Y neuroblastoma cells to A1254. Exposure to A1254 (30.6 μM) for 24 and 48 hours resulted in a time-dependent cell death. Indeed, after 48 hours, MS-275, but not MC-1568, reverted A1254-induced cell death in a dose-dependent manner. Furthermore, A1254 significantly increased HDAC3, but not HDAC1 or HDAC2. Interestingly, REST physically interacted with HDAC3 after A1254 exposure. Chromatin immunoprecipitation assays revealed that MS-275 reverted the increased levels of HDAC3 binding and decreased acetylation of histone H3 within the synapsin-1 promoter region, thus reverting synapsin-1 mRNA reduction. Moreover, REST knockdown by small interfering RNA (siRNA) prevented HDAC3 from binding to the synapsin-1 promoter. Likewise, HDAC3 siRNA significantly reduced A1254-induced cell toxicity in SH-SY5Y cells and cortical neurons. Hence, this study demonstrates that inhibition of HDAC class I attenuates A1254-induced neuronal cell death by preventing HDAC3 binding and histone deacetylation within the synapsin-1 promoter region.

AB - Polychlorinated biphenyl (PCB) exposure has been associated with neurodegenerative diseases, such as Parkinson's disease, amyotrophic lateral sclerosis, and dementia. Neuronal death elicited by the PCB mixture Aroclor 1254 (A1254) has been attributed to an increase in RE-1-silencing transcription factor (REST), which, in turn, correlates with a decrease in the synapsin-1 promoter gene. Although histone deacetylase (HDAC) inhibitors are known to be neuroprotective in several neurologic disorders, the coremechanisms governing this effect are not yet understood. Here, to examine how HDAC class I [N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)aminomethyl]-benzamide (MS-275)] and HDAC class II [3-[5-(3-(3-fluorophenyl)-3-oxopropen-1-yl)-1-methyl-1H-pyrrol-2-yl]-N-hydroxy-2-propenamide (MC-1568)] inhibitors prevent A1254-induced neuronal cell death, we exposed SH-SY5Y neuroblastoma cells to A1254. Exposure to A1254 (30.6 μM) for 24 and 48 hours resulted in a time-dependent cell death. Indeed, after 48 hours, MS-275, but not MC-1568, reverted A1254-induced cell death in a dose-dependent manner. Furthermore, A1254 significantly increased HDAC3, but not HDAC1 or HDAC2. Interestingly, REST physically interacted with HDAC3 after A1254 exposure. Chromatin immunoprecipitation assays revealed that MS-275 reverted the increased levels of HDAC3 binding and decreased acetylation of histone H3 within the synapsin-1 promoter region, thus reverting synapsin-1 mRNA reduction. Moreover, REST knockdown by small interfering RNA (siRNA) prevented HDAC3 from binding to the synapsin-1 promoter. Likewise, HDAC3 siRNA significantly reduced A1254-induced cell toxicity in SH-SY5Y cells and cortical neurons. Hence, this study demonstrates that inhibition of HDAC class I attenuates A1254-induced neuronal cell death by preventing HDAC3 binding and histone deacetylation within the synapsin-1 promoter region.

UR - http://www.scopus.com/inward/record.url?scp=84919766523&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84919766523&partnerID=8YFLogxK

U2 - 10.1124/jpet.114.219345

DO - 10.1124/jpet.114.219345

M3 - Article

VL - 352

SP - 236

EP - 243

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

M1 - A6

ER -