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

Cras, Audrey; Darsin-Bettinger, Diane; Balitrand, N; Cassinat, Bruno; Soulié, Annie; Toubert, Marie Elisabeth; Delva, Laurent; Chomienne, Christine

doi:10.1038/sj.onc.1210178

Cited by 35 publications

(30 citation statements)

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“…Using FTC cell lines with differential response to retinoids, we have previously identified that one of the mechanism inherent to RA resistance may lie in the nonpermissive status of the RARB gene promoter, relieved by histone deacetylase inhibitors (21). This study suggests that along with RARb, RXRg may equally be involved in thyroid oncogenesis, as previously suggested (32) and represents a novel biomarker of RA therapy.…”

Section: Before Treatmentsupporting

confidence: 50%

“…Upregulation of RARB and RXRG expression correlates with achievement of ATRA differentiation in FTC cell lines We have previously shown that FTC133 and FTC238 cell lines present, respectively, low and null expression of RARB mRNA levels (21). In this study, we examined the gene expression levels of the different RARs and RXRs by quantitative reverse transcriptase PCR (RT-PCR).…”

Section: Resultsmentioning

confidence: 99%

“…We have previously reported that lack of RA responsiveness in a FTC cell line was attributable to an altered histone acetylation pattern and could be relieved by combination of ATRA and trichostatin A, a histone deacetylase inhibitor, underscoring the ongoing clinical trials based on differentiation and transcriptional therapy combination (21). To investigate the role of RXR agonist in these patients, we took advantage of the RA-resistant thyroid cancer cell line, FTC238, derived from the metastasis of the patient whose cells, at diagnosis, allowed the establishment of the RAsensitive FTC133 cell line (22).…”

Section: ) Nis Andmentioning

confidence: 99%

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Bexarotene via CBP/p300 Induces Suppression of NF-κB–Dependent Cell Growth and Invasion in Thyroid Cancer

Cras

Politis

Balitrand

et al. 2012

Clinical Cancer Research

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Purpose: Retinoic acid (RA) treatment has been used for redifferentiation of metastatic thyroid cancer with loss of radioiodine uptake. The aim of this study was to improve the understanding of RA resistance and investigate the role of bexarotene in thyroid cancer cells.Experimental Design: A model of thyroid cancer cell lines with differential response to RA was used to evaluate the biological effects of retinoid and rexinoid and to correlate this with RA receptor levels. Subsequently, thyroid cancer patients were treated with 13-cis RA and bexarotene and response evaluated on radioiodine uptake reinduction on posttherapy scan and conventional imaging.Results: In thyroid cancer patients, 13-cis RA resistance can be bypassed in some tumors by bexarotene. A decreased tumor growth without differentiation was observed confirming our in vitro data. Indeed, we show that ligands of RARs or RXRs exert different effects in thyroid cancer cell lines through either differentiation or inhibition of cell growth and invasion. These effects are associated with restoration of RARb and RXRg levels and downregulation of NF-kB targets genes. We show that bexarotene inhibits the transactivation potential of NF-kB in an RXR-dependent manner through decreased promoter permissiveness without interfering with NF-kB nuclear translocation and binding to its responsive elements. Inhibition of transcription results from the release of p300 coactivator from NF-kB target gene promoters and subsequent histone deacetylation.Conclusion: This study highlights dual mechanisms by which retinoids and rexinoids may target cell tumorigenicity, not only via RARs and RXRs, as expected, but also via NF-kB pathway. Clin Cancer Res; 18(2); 442-53. Ó2011 AACR.

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Section: Before Treatmentsupporting

confidence: 50%

Section: Resultsmentioning

confidence: 99%

Section: ) Nis Andmentioning

confidence: 99%

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Bexarotene via CBP/p300 Induces Suppression of NF-κB–Dependent Cell Growth and Invasion in Thyroid Cancer

Cras

Politis

Balitrand

et al. 2012

Clinical Cancer Research

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“…Chromatin immunoprecipitation (ChIP) analysis of CBP/p300 and histone acetylation was performed according to the protocol described by Millipore, as performed by Cras et al (12), using 10 6 cells with a Diagenode sonicator, the Bioruptor, for sonication. ChIP analysis of PML-RAR␣, RAR␣ SMRT, and H3S10p was performed as described by Bruck et al (6).…”

Section: Reagents and Antibodiesmentioning

confidence: 99%

New Role for Granulocyte Colony-Stimulating Factor-Induced Extracellular Signal-Regulated Kinase 1/2 in Histone Modification and Retinoic Acid Receptor α Recruitment to Gene Promoters: Relevance to Acute Promyelocytic Leukemia Cell Differentiation

Cassinat

Zassadowski

Ferry

et al. 2011

Molecular and Cellular Biology

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The induction of the granulocytic differentiation of leukemic cells by all-trans retinoic acid (RA) has been a major breakthrough in terms of survival for acute promyelocytic leukemia (APL) patients. Here we highlight the synergism and the underlying novel mechanism between RA and the granulocyte colony-stimulating factor (G-CSF) to restore differentiation of RA-refractory APL blasts. First, we show that in RA-refractory APL cells (UF-1 cell line), PML-RA receptor alpha (RAR␣) is not released from target promoters in response to RA, resulting in the maintenance of chromatin repression. Consequently, RAR␣ cannot be recruited, and the RA target genes are not activated. We then deciphered how the combination of G-CSF and RA successfully restored the activation of RA target genes to levels achieved in RA-sensitive APL cells. We demonstrate that G-CSF restores RAR␣ recruitment to target gene promoters through the activation of the extracellular signalregulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and the subsequent derepression of chromatin. Thus, combinatorial activation of cytokines and RARs potentiates transcriptional activity through epigenetic modifications induced by specific signaling pathways.

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“…Aberrant histone H3 acetylation due to a DNA hypermethylation consistently correlates with RA resistance in lung cancer cells lines and loss of RARβ expression [79]. In thyroid cancer cells, we have shown that the RARB P2 promoter is in a non permissive status due to absence of histone H3 and H4 acetylation resulting in lack of RA transcriptional activity and differentiation which may be restored upon combination with an HDAC inhibitor [80]. Combination of RA and an HDAC inhibitor leads to a reduction of human renal cell carcinoma proliferation in a xenograft tumor model [81].…”

Section: Rarβ a Tumour Suppressor Genementioning

confidence: 97%

Retinoic Acid Receptors

2010

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Abstract:Retinoids, a group of structural and functional derivatives of vitamin A are known to regulate a large number of essential biological processes such as cell growth, differentiation and death. The retinoic acid (RA) signalling pathway involves the precise regulation of retinoid levels and the control of RA-dependent gene expression in target cells. The effects are mainly mediated by two types of nuclear receptors -retinoic acid receptors and retinoid X receptors -which act as ligand-dependent transcription factors. Different alterations of retinoid receptors or in the RA signalling pathway have been found to be associated with tumorigenesis. The success of retinoid-based differentiation therapy in acute promyelocytic leukemia largely contributes to the understanding of the molecular and pharmacological actions of retinoids. The development of selective receptor retinoids offers a great promising class of compounds for cancer therapy and prevention.9.1. RETINOID RECEPTORS 9.1.1. Structure of Retinoic ReceptorsThe retinoid signal is transduced by two families of nuclear receptors, the family of retinoic acid receptors (RARs) and that of the retinoid X receptors (RXRs). Each family consists of three subtypes: RARα (NR1B1), RARβ (NR1B2), RARγ (NR1B3) and RXRα (NR2B1), RXRβ (NR2B2), RXRγ (NR2B3) [1]. These subtypes are encoded by separate genes (localised to chromosome 17q21, 3p24, 12q13 for RARA, RARB, RARG and to 9q34.3, 6q21.3, 1q22-q23 for RXRA, RXRB, RXRG, respectively) giving rise to multiple isoforms after alternative splicing and promoter usage [2]. There are two major isoforms for RARα (α1 and α2) and RARγ (γ1 and γ2) and four major isoforms for RARβ (β1 and β3 initiated at the P1 promoter and β2 and β4 initiated at the P2 promoter). There are two major isoforms each for RXRα (α1 and α2), RXRβ (β1 and β2), and RXRγ (γ1 and γ2). Retinoid receptors work as RXR/RAR heterodimers or RXR/RXR homodimers [3]. RXR were 237

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

Cited by 35 publications

References 30 publications

Bexarotene via CBP/p300 Induces Suppression of NF-κB–Dependent Cell Growth and Invasion in Thyroid Cancer

Bexarotene via CBP/p300 Induces Suppression of NF-κB–Dependent Cell Growth and Invasion in Thyroid Cancer

New Role for Granulocyte Colony-Stimulating Factor-Induced Extracellular Signal-Regulated Kinase 1/2 in Histone Modification and Retinoic Acid Receptor α Recruitment to Gene Promoters: Relevance to Acute Promyelocytic Leukemia Cell Differentiation

Retinoic Acid Receptors

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