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Epigenetic patterns of the retinoic acid receptor β2 promoter in retinoic acid-resistant thyroid cancer cells

Abstract

Treatment with retinoic acid (RA) is effective to restore radioactive iodine uptake in metastases of a small fraction of thyroid cancer patients. In order to find predictive markers of response, we took advantage of two thyroid cancer cell lines, FTC133 and FTC238, with low RA-receptor (RAR)β expression but differing in their response to RA. We report that in both cell lines, RA signalling pathways are functional, as transactivation of an exogenous RARβ2 promoter is effective in the presence of pharmacological concentrations of all-trans RA, and enhanced in RA-resistant FTC238 cells after ectopical expression of RARβ, suggesting a defective endogenous RARβ2 promoter in these cells. Further analyses show that whereas the RARβ2 promoter is in an unmethylated permissive status in both FTC133 and FTC238 cells, it failed to be associated with acetylated forms of histones H3 or H4 in FTC238 cells upon RA treatment. Incubation with a histone deacetylase inhibitor, alone or in combination with RA, restored histone acetylation levels and reactivated RARβ and differentiation marker Na+/I symporter gene expression. Thus, histone modification patterns may explain RA-refractoriness in differentiated thyroid cancer patients and suggest a potential benefit of combined transcriptional and differentiation therapies.

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Abbreviations

ATRA:

all-trans-retinoic acid

AZA:

5-aza-2′-deoxycytidine

DTC:

differentiated thyroid cancer

FTC:

follicular thyroid carcinoma

NIS:

Na+/I symporter

RA:

retinoic acid

RAR:

retinoic acid receptor

RARE:

retinoic acid response element

TG:

thyroglobulin

TPO:

thyroid peroxidase

TSA:

trichostatin A

5′DI:

5′-deiodinase

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Acknowledgements

We gratefully acknowledge C Schmutzler for providing FTC cells and H de Thé for plasmids. We express our thanks to J Maes and M Goodhardt for helpful discussions on chromatin immunoprecipitation assay. We thank E Savariau, member of the ‘Service d'Infographie’ of the IUH, for excellent artworks. This work was supported by funds from the Association pour la Recherche sur le Cancer (ARC) and the Ligue nationale contre le cancer (Comité de Paris). AC holds an INSERM Researcher Grant position.

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Correspondence to C Chomienne.

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Cras, A., Darsin-Bettinger, D., Balitrand, N. et al. Epigenetic patterns of the retinoic acid receptor β2 promoter in retinoic acid-resistant thyroid cancer cells. Oncogene 26, 4018–4024 (2007). https://doi.org/10.1038/sj.onc.1210178

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