1. ¹INSERM, UMR S 718, Université Denis Diderot-Paris 7, Institut Universitaire d'Hématologie, Paris, France
2. ²Unité de Biologie Cellulaire, Hôpital Saint-Louis, AP-HP, Paris, France
3. ³Service de Médecine Nucléaire, Hôpital Saint-Louis, AP-HP, Paris, France

Correspondence: Professor C Chomienne, INSERM, UMR S 718, IUH, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France. E-mail: christine.chomienne@sls.ap-hop-paris.fr

⁴These authors contributed equally to this work.

⁵These authors share equal responsibility for this work.

Received 23 December 2005; Revised 11 October 2006; Accepted 20 October 2006; Published online 8 January 2007.

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) 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 RAR₂ promoter is effective in the presence of pharmacological concentrations of all-trans RA, and enhanced in RA-resistant FTC238 cells after ectopical expression of RAR, suggesting a defective endogenous RAR₂ promoter in these cells. Further analyses show that whereas the RAR₂ 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 RAR 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.