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RAR-mediated epigenetic control of the cytochrome P450 Cyp26a1 in embryocarcinoma cells

Oncogene volume 25, pages 1400–1407 (2006)Cite this article

Abstract

Retinoic acid (RA) is a signaling molecule that plays a pivotal role in major cellular processes and vertebrate development. RA action is mediated by specialized transcription factors, the nuclear RA receptors (RARs), which regulate the transcription of genes containing a RA-responsive element (RARE). Here we demonstrate that the genes for the RA-receptor RARβ2 and the cytochrome P450 RA-specific hydrolase Cyp26a1 involved in RA catabolism are coordinately regulated by RA. We found that both RARβ2 and Cyp26a1 genes are epigenetically silenced in the absence of DNA methylation in RAC65, a P19 embryocarcinoma cell line derivative carrying a dominant-negative RARα mutant and resistant to the growth-inhibitory and differentiation effects of RA. In response to RA, RARβ2 transcription is epigenetically regulated by RARα. Similarly, we found that Cyp26a1 transcription is epigenetically regulated by RARβ2. Knocking down RARβ2 transcription by RNA interference in wild-type P19 cells, with an intact RARα, induced Cyp26a1 transcriptional repression in the absence of DNA methylation. Concomitantly, cells developed RA resistance and did not undergo RA-induced neuron differentiation. Apparently, RARα, RARβ2 and Cyp26a1 are components of a RA-regulated gene network. Factors affecting an upstream gene of the network can trigger repressive chromatin changes – which are propagated in a domino fashion – at downstream genes of the network. This study also shows that chromatin inactivity, and consequent transcriptional silencing, can be achieved in the absence of DNA methylation.

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Acknowledgements

We thank Dr Paul T van der Saag for kindly providing the embryocarcinoma cell lines, Drs Giulia Somenzi and MingQiang Ren for critical discussion and suggestions. This work was partially supported by a grant from the Association for Research of Childhood Cancer (AROCC) to NS.

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  1. Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA

    S Pozzi, S Rossetti, G Bistulfi & N Sacchi

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  1. S Pozzi
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  2. S Rossetti
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Correspondence to N Sacchi.

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Pozzi, S., Rossetti, S., Bistulfi, G. et al. RAR-mediated epigenetic control of the cytochrome P450 Cyp26a1 in embryocarcinoma cells. Oncogene 25, 1400–1407 (2006). https://doi.org/10.1038/sj.onc.1209173

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