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Histone Deacetylase Inhibitors Regulate Retinoic Acid Receptor ß Expression in Neuroblastoma Cells by Both Transcriptional and Posttranscriptional Mechanisms

Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28029 Madrid, Spain

Address all correspondence and requests for reprints to: Ana Aranda, Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas Universidad Autónoma de Madrid, Arturo Duperier 4, 28029 Madrid, Spain. E-mail: aaranda{at}iib.uam.es.

The retinoic acid receptor ß (RARß) is a retinoic acid (RA)-inducible tumor suppressor, which plays an important role in the arrest of neuroblastoma cell growth. Using human neuroblastoma SH-SY5Y cells, we have examined the regulation of RARß expression by histone deacetylase inhibitors (HDACi), considered to be promising agents in anticancer therapy. Our results show that HDACi cooperated with RA to increase RARß mRNA levels and to activate the RARß2 promoter in transient transfection assays. Chromatin immunoprecipitation assays showed that the basal RARß2 promoter that contains the RA response element was refractory to acetylation by both HDACi and RA. In addition, HDACi caused a transient increase in acetylation of a downstream RARß2 region, even though global histones remain hyperacetylated after a prolonged treatment with the inhibitors. RA potentiated this response and maintained acetylation for a longer period. Despite the cooperation of RA with HDACi to increase transcription of the RARß gene, these inhibitors caused a paradoxical reduction of the cellular levels of the RARß protein in cells treated with the retinoid. This reduction is secondary to a change in the protein half-life that is decreased by the HDACi due to increased ubiquitin-independent proteasomal degradation. These results show that HDACi regulate expression of the tumor suppressor gene RARß by both transcriptional and posttranscriptional mechanisms and might then modulate sensitivity to the retinoid in neuroblastoma cells.

NURSA Molecule Pages Link:

Nuclear Receptors:   RARβ

Ligands:   all-trans-Retinoic acid