ABSTRACT
Title
The transcription factor REST is a novel molecular target for the neurotoxic effect of the polychlorinated biphenyl mixture Aroclor 1254 in neuroblastoma SH-SY5Y cells
Authors
Luigi Formisano1,3, Natascia Guida 1, Stefania Cocco 1, Agnese Secondo 1, Rossana Sirabella 2, Luca Ulianich 4, Flora Paturzo 4, Gianfranco Di Renzo 1, and Lorella MT Canzoniero 1,3.
1Division of Pharmacology, Dept. Of Neuroscience, School of Medicine, “Federico II” University of Naples, Via Sergio Pansini 5, Naples 80131Italy ; 2 Fondazione IRCSS SDN, Naples Italy; 3Division of Pharmacology, Department of Biological and Environmental Sciences, University of Sannio, Via Port’Arsa 11 82100 Benevento, Italy;4Department of Cellular and Molecular Biology and Pathology, Federico II University of Naples, Via Sergio Pansini 5, Naples 80131, Italy
1Division of Pharmacology, Dept. Of Neuroscience, School of Medicine, “Federico II” University of Naples, Via Sergio Pansini 5, Naples 80131Italy ; 2 Fondazione IRCSS SDN, Naples Italy; 3Division of Pharmacology, Department of Biological and Environmental Sciences, University of Sannio, Via Port’Arsa 11 82100 Benevento, Italy;4Department of Cellular and Molecular Biology and Pathology, Federico II University of Naples, Via Sergio Pansini 5, Naples 80131, Italy
Abstract
Polychlorinated biphenyls (PCBs) are ubiquitous environmental toxicants, long-term chronic exposure to which cause neurocognitive anomalies. The transcription factor REST (RE1-silencing transcription factor) plays a critical role in neuronal phenotype elaboration in both neural progenitor and non-neural cells. Here, we investigated the possible relationship between PCBs and REST in neuroblastoma SH-SY5Y cells. In these cells, chronic exposure to the PCB mixture Aroclor 1254 (A-1254, 5-30 μg/ml) caused dose-dependent cell death via the induction of calpain but not of caspase-3, and the calpain inhibitor calpeptin prevented this A1254-induced cell death. Furthermore, A-1254 enhanced REST mRNA and protein expressions after both 24 and 48 hrs. REST down-regulation by RNA interference prevented A-1254-induced cell death. In addition, A1254 enhanced REST association to the Synapsin-1 gene promoter, and knocking-down Synapsin 1 potentiated A1254-induced cell death. The two REST cofactors REST corepressor (Co-Rest) and mammalian SIN3 homolog A transcription regulator (mSin3-A) were up-regulated by A1254 (10 µg/ml) which also decreased the acetylations of histone proteins H3 and H4. Interestingly, the hystone deacetylases inhibitor trichostatin Aprevented such decreases in H3 and H4 acetylations and prevented the A1254-induced neurotoxic effect.
Collectively, these results suggest that A-1254 exerted its toxic effect via REST through Synapsin 1 down-regulation and decreases in H3 and H4 histone protein acetylations