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Unlocking the potential of retinoic acid in anticancer therapy.

Schenk T, Stengel S, Zelent A - Br. J. Cancer (2014)

Bottom Line: All-trans-retinoic acid (ATRA) is a physiologically active metabolite of vitamin A.Recent studies directed to improve ATRA responsiveness in non-APL AML seem to indicate that the lack of effective ATRA response in these tumours may be primarily due to aberrant epigenetics, which negatively affect ATRA-regulated gene expression and its antileukaemic activity.Epigenetic reprogramming could potentially restore therapeutic effects of ATRA in all AML subtypes.

View Article: PubMed Central - PubMed

Affiliation: Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, 123 Old Brompton Road, SW7 3RP London, UK.

ABSTRACT
All-trans-retinoic acid (ATRA) is a physiologically active metabolite of vitamin A. Its antitumour activities have been extensively studied in a variety of model systems and clinical trials; however, to date the only malignancy responsive to ATRA treatment is acute promyelocytic leukaemia (APL) where it induces complete remission in the majority of cases when administered in combination with light chemotherapy and/or arsenic trioxide. After decades of studies, the efficacy of ATRA to treat other acute myeloid leukaemia (AML) subtypes and solid tumours remains poor. Recent studies directed to improve ATRA responsiveness in non-APL AML seem to indicate that the lack of effective ATRA response in these tumours may be primarily due to aberrant epigenetics, which negatively affect ATRA-regulated gene expression and its antileukaemic activity. Epigenetic reprogramming could potentially restore therapeutic effects of ATRA in all AML subtypes. This review discusses the current progresses in the understanding how ATRA can be utilised in the therapy of non-APL AML and other cancers.

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Related in: MedlinePlus

Structure and function of the retinoic acid receptor alpha gene and protein upon binding of RA. (A) RARA, in common with other RAR genes, encodes two major isoforms that differ in their promoters (P1 and P2) and A region sequences, but are identical in their B–F region sequences. The B–F regions contain DNA (DBD) and ligand binding (LBD) domains as well as structural motifs responsible for dimerisation, co-repressor interaction and ligand-dependent trans-activation. (B) Schematic representation of the RARα LBD, which is composed of 12 alpha helices (colour coded and labelled as H1–H12). The ribbon diagrams of the crystal structures of un-liganded RXRα LBD (3A9E) and the liganded RARα LBD (3KMR) are illustrating the principle of RAR activation. In the un-liganded state, helices H3 and H4 provide a binding site for co-repressors. Upon ligand binding H3 and H4 undergo conformational changes leading to a destruction of the co-repressor binding site. Helix H12 moves towards a ligand binding pocket and generates a defined binding surface for co-activators such as p160. (C) RARs possess the capacity to function as a molecular switch; when not bound by ligand, they complex with co-repressors, such as N-CoR or SMRT, and HDACs to actively inhibit gene expression. Upon ATRA binding, co-repressors are released and co-activators, including DRIP/TRAP/ARC or mediator-containing complexes as well as HATs, are recruited to decompress chromatin and activate transcription of target genes.
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fig1: Structure and function of the retinoic acid receptor alpha gene and protein upon binding of RA. (A) RARA, in common with other RAR genes, encodes two major isoforms that differ in their promoters (P1 and P2) and A region sequences, but are identical in their B–F region sequences. The B–F regions contain DNA (DBD) and ligand binding (LBD) domains as well as structural motifs responsible for dimerisation, co-repressor interaction and ligand-dependent trans-activation. (B) Schematic representation of the RARα LBD, which is composed of 12 alpha helices (colour coded and labelled as H1–H12). The ribbon diagrams of the crystal structures of un-liganded RXRα LBD (3A9E) and the liganded RARα LBD (3KMR) are illustrating the principle of RAR activation. In the un-liganded state, helices H3 and H4 provide a binding site for co-repressors. Upon ligand binding H3 and H4 undergo conformational changes leading to a destruction of the co-repressor binding site. Helix H12 moves towards a ligand binding pocket and generates a defined binding surface for co-activators such as p160. (C) RARs possess the capacity to function as a molecular switch; when not bound by ligand, they complex with co-repressors, such as N-CoR or SMRT, and HDACs to actively inhibit gene expression. Upon ATRA binding, co-repressors are released and co-activators, including DRIP/TRAP/ARC or mediator-containing complexes as well as HATs, are recruited to decompress chromatin and activate transcription of target genes.

Mentions: Similarly to other key developmental regulators, RARs possess the capacity to function as a molecular switch; when not bound by ligand, they form a complex with co-repressors such as N-CoR (negative co-regulator) or SMRT (silencing mediator for retinoid and thyroid hormone receptors), and histone deacetylases (HDACs) to actively inhibit gene expression (Figure 1). Upon ATRA binding, co-repressors are released and co-activators, including histone acetyltransferases (HATs), DRIP/TRAP/ARC, or mediator-containing complexes are recruited to decompress chromatin and activate transcription of target genes (Glass and Rosenfeld, 2000). To date, three different RAR and retinoid X (or rexinoid) receptor (RXR) genes have been characterised (RARA, RARB, and RARG), each encoding multiple N-terminal protein isoforms. Retinoid X (or rexinoid) receptors, which bind 9-cis-retinoic acid (9-cis-RA) with high affinity, serve as obligatory heterodimerisation partners for RARs. RARA, in common with other RAR genes, encodes two major isoforms (Figure 1) that differ in their A region sequence that contribute to transcriptional regulation in a ligand-independent and promoter-specific manner (Leid et al, 1992). These isoforms are identical in their B to F region sequence, which contain DNA (DBD) and ligand binding (LBD) domains as well as structural motifs responsible for dimerisation, co-repressor interaction, and ligand-dependent trans-activation. Expression of the RARα2, RARβ2 and possibly also RARγ2 isoforms is under control of promoters that are inducible by ATRA. Activation of transcription by RARs is intrinsically linked to their proteasome-mediated degradation (Giannì et al, 2002) and upregulation of RARα2, RARβ2, and RARγ2 isoform expression by ATRA may therefore have been evolutionarily selected and conserved to renew expression of a given receptor to sustain gene activation and the physiological effects of ATRA over an extended period of time.


Unlocking the potential of retinoic acid in anticancer therapy.

Schenk T, Stengel S, Zelent A - Br. J. Cancer (2014)

Structure and function of the retinoic acid receptor alpha gene and protein upon binding of RA. (A) RARA, in common with other RAR genes, encodes two major isoforms that differ in their promoters (P1 and P2) and A region sequences, but are identical in their B–F region sequences. The B–F regions contain DNA (DBD) and ligand binding (LBD) domains as well as structural motifs responsible for dimerisation, co-repressor interaction and ligand-dependent trans-activation. (B) Schematic representation of the RARα LBD, which is composed of 12 alpha helices (colour coded and labelled as H1–H12). The ribbon diagrams of the crystal structures of un-liganded RXRα LBD (3A9E) and the liganded RARα LBD (3KMR) are illustrating the principle of RAR activation. In the un-liganded state, helices H3 and H4 provide a binding site for co-repressors. Upon ligand binding H3 and H4 undergo conformational changes leading to a destruction of the co-repressor binding site. Helix H12 moves towards a ligand binding pocket and generates a defined binding surface for co-activators such as p160. (C) RARs possess the capacity to function as a molecular switch; when not bound by ligand, they complex with co-repressors, such as N-CoR or SMRT, and HDACs to actively inhibit gene expression. Upon ATRA binding, co-repressors are released and co-activators, including DRIP/TRAP/ARC or mediator-containing complexes as well as HATs, are recruited to decompress chromatin and activate transcription of target genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4260020&req=5

fig1: Structure and function of the retinoic acid receptor alpha gene and protein upon binding of RA. (A) RARA, in common with other RAR genes, encodes two major isoforms that differ in their promoters (P1 and P2) and A region sequences, but are identical in their B–F region sequences. The B–F regions contain DNA (DBD) and ligand binding (LBD) domains as well as structural motifs responsible for dimerisation, co-repressor interaction and ligand-dependent trans-activation. (B) Schematic representation of the RARα LBD, which is composed of 12 alpha helices (colour coded and labelled as H1–H12). The ribbon diagrams of the crystal structures of un-liganded RXRα LBD (3A9E) and the liganded RARα LBD (3KMR) are illustrating the principle of RAR activation. In the un-liganded state, helices H3 and H4 provide a binding site for co-repressors. Upon ligand binding H3 and H4 undergo conformational changes leading to a destruction of the co-repressor binding site. Helix H12 moves towards a ligand binding pocket and generates a defined binding surface for co-activators such as p160. (C) RARs possess the capacity to function as a molecular switch; when not bound by ligand, they complex with co-repressors, such as N-CoR or SMRT, and HDACs to actively inhibit gene expression. Upon ATRA binding, co-repressors are released and co-activators, including DRIP/TRAP/ARC or mediator-containing complexes as well as HATs, are recruited to decompress chromatin and activate transcription of target genes.
Mentions: Similarly to other key developmental regulators, RARs possess the capacity to function as a molecular switch; when not bound by ligand, they form a complex with co-repressors such as N-CoR (negative co-regulator) or SMRT (silencing mediator for retinoid and thyroid hormone receptors), and histone deacetylases (HDACs) to actively inhibit gene expression (Figure 1). Upon ATRA binding, co-repressors are released and co-activators, including histone acetyltransferases (HATs), DRIP/TRAP/ARC, or mediator-containing complexes are recruited to decompress chromatin and activate transcription of target genes (Glass and Rosenfeld, 2000). To date, three different RAR and retinoid X (or rexinoid) receptor (RXR) genes have been characterised (RARA, RARB, and RARG), each encoding multiple N-terminal protein isoforms. Retinoid X (or rexinoid) receptors, which bind 9-cis-retinoic acid (9-cis-RA) with high affinity, serve as obligatory heterodimerisation partners for RARs. RARA, in common with other RAR genes, encodes two major isoforms (Figure 1) that differ in their A region sequence that contribute to transcriptional regulation in a ligand-independent and promoter-specific manner (Leid et al, 1992). These isoforms are identical in their B to F region sequence, which contain DNA (DBD) and ligand binding (LBD) domains as well as structural motifs responsible for dimerisation, co-repressor interaction, and ligand-dependent trans-activation. Expression of the RARα2, RARβ2 and possibly also RARγ2 isoforms is under control of promoters that are inducible by ATRA. Activation of transcription by RARs is intrinsically linked to their proteasome-mediated degradation (Giannì et al, 2002) and upregulation of RARα2, RARβ2, and RARγ2 isoform expression by ATRA may therefore have been evolutionarily selected and conserved to renew expression of a given receptor to sustain gene activation and the physiological effects of ATRA over an extended period of time.

Bottom Line: All-trans-retinoic acid (ATRA) is a physiologically active metabolite of vitamin A.Recent studies directed to improve ATRA responsiveness in non-APL AML seem to indicate that the lack of effective ATRA response in these tumours may be primarily due to aberrant epigenetics, which negatively affect ATRA-regulated gene expression and its antileukaemic activity.Epigenetic reprogramming could potentially restore therapeutic effects of ATRA in all AML subtypes.

View Article: PubMed Central - PubMed

Affiliation: Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, 123 Old Brompton Road, SW7 3RP London, UK.

ABSTRACT
All-trans-retinoic acid (ATRA) is a physiologically active metabolite of vitamin A. Its antitumour activities have been extensively studied in a variety of model systems and clinical trials; however, to date the only malignancy responsive to ATRA treatment is acute promyelocytic leukaemia (APL) where it induces complete remission in the majority of cases when administered in combination with light chemotherapy and/or arsenic trioxide. After decades of studies, the efficacy of ATRA to treat other acute myeloid leukaemia (AML) subtypes and solid tumours remains poor. Recent studies directed to improve ATRA responsiveness in non-APL AML seem to indicate that the lack of effective ATRA response in these tumours may be primarily due to aberrant epigenetics, which negatively affect ATRA-regulated gene expression and its antileukaemic activity. Epigenetic reprogramming could potentially restore therapeutic effects of ATRA in all AML subtypes. This review discusses the current progresses in the understanding how ATRA can be utilised in the therapy of non-APL AML and other cancers.

Show MeSH
Related in: MedlinePlus