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

Abstract Sodium phenylacetate (NaPA) has been shown to synergize with retinoic acid (RA) in inducing the differentiation of human neuroblastoma cells. Our studies indicated that NaPA can impact on the RA differentiation program by upregulating nuclear retinoic acid receptor-β (RARβ) expression. We have found that NaPA does not alter the half-life of RARβ mRNA; thus, increased stability of mRNA levels does not contribute to NaPA induction. In contrast, NaPA was able to specifically activate a reporter gene construct (ΔSVβRE-CAT) which contains a retinoic acid response element (RAREβ) that is located in the RARβ promoter. Activation of ΔSVβRE-CAT by NaPA also occurred in neuroblastoma cells cotransfected with a nuclear retinoic acid receptor expression vector, demonstrating the independence of this activation on cellular RAR levels. Taken together, our findings suggest that induction of RARβ by NaPA is regulated at the level of transcription and mediated through the retinoic acid response element, RAREβ. This effect may account, at least in part, for the strong synergy between NaPA and RA in promoting neuroblastoma differentiation.

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