Transcriptional Upregulation of Retinoic Acid Receptor β (RARβ) Expression by Phenylacetate in Human Neuroblastoma Cells

Abstract The retinoic acid receptor β (RARβ) 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 RARβ expression by histone deacetylase inhibitors (HDACi), considered to be promising agents in anticancer therapy. Our results show that HDACi cooperated with RA to increase RARβ mRNA levels and to activate the RARβ2 promoter in transient transfection assays. Chromatin immunoprecipitation assays showed that the basal RARβ2 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 RARβ2 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 RARβ gene, these inhibitors caused a paradoxical reduction of the cellular levels of the RARβ 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 RARβ by both transcriptional and posttranscriptional mechanisms and might then modulate sensitivity to the retinoid in neuroblastoma cells.

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Identification and Characterization of All-trans-Retinoic Acid Receptor Transcripts and Receptor Protein in Human Neuroblastoma Cells

Archives of Biochemistry and Biophysics ◽

10.1006/abbi.1993.1095 ◽

1993 ◽

Vol 300 (2) ◽

pp. 684-693 ◽

Cited By ~ 26

Author(s):

M. Clagettdame ◽

T.J. Verhalen ◽

J.L. Biedler ◽

J.J. Repa

Keyword(s):

Retinoic Acid ◽

Retinoic Acid Receptor ◽

Neuroblastoma Cells ◽

Receptor Protein ◽

Human Neuroblastoma Cells ◽

Human Neuroblastoma ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Identification And Characterization

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Regulation of c-myb expression in human neuroblastoma cells during retinoic acid-induced differentiation.

Molecular and Cellular Biology ◽

10.1128/mcb.8.4.1677 ◽

1988 ◽

Vol 8 (4) ◽

pp. 1677-1683 ◽

Cited By ~ 54

Author(s):

C J Thiele ◽

P S Cohen ◽

M A Israel

Keyword(s):

Retinoic Acid ◽

Fetal Development ◽

Neuroblastoma Cell ◽

Neuroblastoma Cells ◽

Human Neuroblastoma Cell ◽

Human Neuroblastoma Cells ◽

Human Neuroblastoma ◽

Hematopoietic Lineage ◽

Specific Manner ◽

Neuroblastoma Cell Lines

We detected expression of the c-myb proto-oncogene, which was initially thought to be expressed in a tissue-specific manner in cells of hematopoietic lineage, in human tissues of neuronal origin. Since the level of c-myb expression declined during fetal development, we studied the regulation of its expression in human neuroblastoma cell lines induced to differentiate by retinoic acid. The expression of c-myb declined during the maturation of neuroblastoma cells, and this change was mediated by a decrease in c-myb transcription.

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