Regulation of vitamin D receptor expression by retinoic acid receptor alpha in acute myeloid leukemia cells. Issue 159 (May 2016)

• Record Type: Journal Article
• Authors: Marchwicka, Aleksandra; Cebrat, Małgorzata; Łaszkiewicz, Agnieszka; Śnieżewski, Łukasz; Brown, Geoffrey; Marcinkowska, Ewa
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 159(2016)
• Page Start: 121
• Page End: 130
• Publication Date: 2016-05
• Subjects: Vitamin D receptor -- Retinoic acid receptor alpha -- Expression -- mRNA -- Target gene -- Differentiation; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2016.03.013
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: We show that RARα is responsible for regulating VDR transcription in AML cells. We show that the VDR transcriptional 1a variant is regulated by RARα in AML cells. VDR gene expression is low in the absence of RARα agonist in KG1 cells. We identify a VDR transcript variant originating from a new exon 1 g. The cis -regulatory element, used by RARα, is located in the promoter region of exon 1a. Abstract: Acute myeloid leukemia (AML) is the predominant acute leukemia among adults, characterized by an accumulation of malignant immature myeloid precursors. A very promising way to treat AML is differentiation therapy using either all- trans -retinoic acid (ATRA) or 1, 25-dihydroxyvitamin D3 (1, 25D), or the use of both these differentiation-inducing agents. However, the effect of combination treatment varies in different AML cell lines, and this is due to ATRA either down- or up-regulating transcription of vitamin D receptor (VDR) in the cells examined. The mechanism of transcriptional regulation of VDR in response to ATRA has not been fully elucidated. Here, we show that the retinoic acid receptor α (RARα) is responsible for regulating VDR transcription in AML cells. We have shown that a VDR transcriptional variant, originating in exon 1a, is regulated by RARα agonists in AML cells. Moreover, in cells with a high basal level of RARα protein, the VDR gene is transcriptionally repressed as long as RARα agonist is absent. In these cells down-regulation of the level of RARα leads to increased expression of VDR . We consider that our findings provide a mechanistic background to explain the different outcomes from treating AML cell lines with a combination of ATRA and 1, 25D.