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The Role and Epigenetic Modification of the Retinoic Acid Receptor

  • Yukihiko Kato
Living reference work entry

Abstract

Dietary vitamin A is converted to retinoids, including retinal, retinol, and retinoic acid, in the metabolic pathway. Two types of retinoic acid exist in the cell nucleus along with two types of receptor, the retinoic acid receptor (RAR) and retinoic X receptor (RXR) each of which has three subtypes, α, β, and γ. Retinoic acid receptors are involved in a wide variety of functions including mediating cell differentiation, tissue growth, blood vessel formation, the emotional and cognitive functions, and tumor suppression.

RARβ, a tumor suppressor gene, is epigenetically suppressed in most cancers. Epigenetic modification of RAR in many cancers includes DNA methylation and histone hypoacetylation. Histone deacetylase inhibitor and RA restore RAR expression and have shown a strong antitumor effect. The epigenetic modification of RAR could have clinical applications such as in diagnosing malignancies.

In the future, as many other types of epigenetic modifications become better understood, we can expect their diagnostic and therapeutic applications to be greatly expanded.

Keywords

Vitamin A All-trans retinoic acid Retinoic acid receptor 9-cis-retinoic acid Retinoic X receptor Retinoid Tumor suppressor gene RARβ2 Histone deacetylase Hypoacetylation 

List of Abbreviations

ATRA

All-trans retinoic acid

CRA

9-cis-retinoic acid

HDAC

Histone deacetylase

RA

Retinoic acid

RAR

Retinoic acid receptor

RARE

Receptor responsive element

RXR

Retinoic X receptor

Introduction

Vitamin A and Retinoid

The importance of vitamin A in vision was first noticed in the 1950s. Since then, vitamin A has attracted considerable attention as a strong inducer of cell differentiation. Nearly two decades of studies have revealed that the gene expression of this lipophilic vitamin was regulated epigenetically via the chromatin structure.

Dietary vitamin A is converted to all-trans retinoic (ATRA) acid and 9-cis-retinoic acid (CRA) via retinal in the metabolic pathway. Two types of retinoic acid receptor exist in the cell nucleus along with two types of receptor, RAR and retinoic X receptor (RXR), each of which has three subtypes, α, β, and γ. The heterodimer of RAR and RXR binds to the retinoic acid receptor responsive element (RARE) and regulates the transcriptional activity of the target genes (Fig. 1).
Fig. 1

Intracellular translocation of vitamin A. Dietary vitamin A, which results from the transformation of provitamin A (β-carotene), becomes all-trans retinoic acid (ATRA) and 9-cis-retinoic acid (CRA) via retinal in the metabolic pathway. Two types of retinoic acid exist in the cell nucleus together with two types of receptor, namely, the retinoic acid receptor (RAR) and retinoic X receptor (RXR). The heterodimer of RAR and RXR binds to the retinoic acid receptor responsive element (RARE) and regulates the transcriptional activity of the target genes

A “retinoid,” a derivative of a monocyclic compound, functions in a manner similar to retinoic acid via specific receptors. This current definition is remarkable in that it anticipated the discovery of retinoic acid receptor (RAR). The best-known retinoids are retinal, retinol, and retinoic acid (Fig. 2).
Fig. 2

Chemical structure of vitamin A

Retinoids perform various functions throughout the body and are involved in the maintenance of eye and skin health, the formation of sperm, normal functioning of the immune system, the activation of tumor suppressor genes, and cell differentiation. Retinoic acid is involved in the switching between proliferation and differentiation in various neural stem cells in vitro. Retinoids are also used for the treatment of a number of dermatological diseases including psoriasis, lymphoma of the skin, acne, photoaging, and skin wrinkles.

The Retinoic Acid Receptor

Retinoic acid receptors mediate a wide variety of functions including tissue growth, blood vessel formation, the regulation of the emotional and cognitive functions, and tumor suppression.

Angiogenesis of Blood Vessels

The RAR agonists, all-trans retinoic acid (ATRA) and Am580, upregulate angiogenesis by producing nitric oxide via the phosphoinositide 3-kinase (PI3K)/Akt pathway (Uruno et al. 2005). According to one study, this angiogenic effect was mediated in vitro by the production of vascular endothelial growth factor (VEGF) via the expression of VEGF receptor 2 on endothelial cells (Saito et al. 2007). Similarly tazarotene, which is a RAR agonist but not a RXR agonist, was found to promote angiogenesis and wound healing (Al Haj Zen et al. 2016).

Emotional and Cognitive Functions

A study by Etchamendy et al. (2001) found that RAR normalized age-related memory deficits in mice. Similarly, Mingaud et al. (2008) also found that RAR improved short-term/working memory organization and long-term declarative memory encoding in mice. Vitamin A deficiency causes amyloid β deposition in the adult rat brain by disrupting the retinoid signaling pathway (Corcoran et al. 2004). RA rescued memory deficits in an Alzheimer’s disease transgenic mouse model by downregulating the amyloid precursor protein and tau protein in the brain (Ding et al. 2008).

Tumor Suppressive Function

RA is involved in cell differentiation as described above. However, RARβ, a tumor suppressor gene, is epigenetically suppressed in most cancers. This next chapter will discuss a number of studies that have been done on the epigenetics of RARβ activity and review some of the possible clinical implications.

Epigenetics of RAR

Most studies of RAR involving epigenetics have been performed in the field of oncology. Sirchia et al. (2000) first reported that the loss of RARβ in breast cancer was due to DNA methylation of the promoter site and suggested the possibility of a repressive mechanism other than DNA methylation after a demethylating agent failed to restore the expression of RARβ. DNA methylation has been found to suppress RAR expression (Moison et al. 2013) in gastric cancer (Hayashi et al. 2001), esophageal squamous cell carcinoma (Liu et al. 2005), cervical cancer (Zhang et al. 2007), breast cancer (Fang et al. 2015; Sun et al. 2011), and bladder cancer (Berrada et al. 2012). Furthermore, the tobacco smoke carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, induced RARβ hypermethylation in esophageal squamous epithelial cells (Wang et al. 2012).

Some reports have demonstrated that the epigenetic modification of RAR included DNA methylation and hypoacetylation of histone in prostate cancer (Nakayama et al. 2001; Qian et al. 2005), renal cell carcinoma (Wang et al. 2005), and melanoma (Kato et al. 2007). In these studies, histone deacetylase (HDAC) inhibitor and RA restored the expression of RAR and the antitumor effect of RA. Kato et al. showed that histone acetylation was superior to DNA methylation in restoring RAR expression in cutaneous T cell lymphoma and demonstrated the double antitumor effect of HDAC inhibitor and RA (Fig. 3) (Kato et al. 2016). These findings might explain why the demethylating agent failed to restore the expression of RAR in the study by Sirchia et al. (2000).
Fig. 3

Reexpression of RARβ2 induced by histone deacetylase (HDAC) inhibitor. (a) Retinoic acid receptor (RAR) β2 was repressed epigenetically. (b) RARβ2 expression was restored by HDAC inhibitor and had a double antitumor effect via HDAC inhibitor and retinoic acid

A number of studies have demonstrated that the deacetylation, rather than the methylation, of the RAR promoter repressed RAR expression via the hypomethylation of the promoter itself. Histone deacetylase inhibitor alone, which does not affect the methylation status, restored RAR in thyroid cancer cells (Cras et al. 2007) and cervical cancer cells (Zhang et al. 2007).

Some studies have treated RARβ2 as a tumor suppressor gene. Widschwendter was the first to observe that RARβ2 was apparently methylated in breast cancer and unmethylated in nonneoplastic breast tissue or normal tissue. Widschwendter thus suggested that the treatment of cancer patients with demethylating agents followed by retinoic acid might constitute a new chemopreventive therapeutic method (Widschwendter et al. 2001). However, Kato et al. pointed that RARβ2 was a tumor suppressor gene regulated by histone acetylation rather than by DNA methylation (Kato et al. 2016, p. 58).

Other studies have pointed that RAR is regulated epigenetically in concert with other genes. He et al. (2009) showed that inducing the overexpression of Myc, an oncogene, inhibited RARβ expression by methylation in a benign prostate epithelial cell line (He et al. 2009). One of the target genes of promyelocytic leukemia zinc finger-retinoic acid receptor alpha (PLZF-RARalpha), an oncogenic transcriptional repressor, is an RAR element in leukemogenesis (Choi et al. 2014). RARβ and p16 were downregulated in epithelial ovarian carcinomas and low-malignant potential tumors by methylation while no methylation was observed in normal ovarian tissue (Bhagat et al. 2014).

Epigenetic modification of RAR could have clinical applications. Since the promoter hypermethylation of RARβ2 was closely associated with prostate cancer rather than prostate hypertrophy, the methylation status of RARβ2 might be useful for clinical diagnosis (Dumache et al. 2012). Pirouzpanah et al. reported that hypermethylated RARβ2 was associated with younger age in breast cancer patients, and that hypermethylation of estrogen receptor (ER) alpha was associated with smoking, duration of estradiol exposure, ER-negative tumor, and body mass index (Pirouzpanah et al. 2010). Cassinat interestingly found that in an acute promyelocytic leukemia (APL) patient, granulocyte colony-stimulating factor (G-CSF) restored RAR alpha expression via the activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and subsequent histone phosphorylation, histone acetyltransferase activity, and histone acetylation (Cassinat et al. 2011).

The relationship between viral infections and RARβ2 is complicated. Human papilloma virus type 16 (HPV16) increased RARβ mRNA and protein in vitro and in vivo in cervical cancer cells (Gutierrez et al. 2015). On the other hand, in a model of HPV-18-positive HeLa cells, ectopic expression of RARβ2 decreased HPV-18 transcription, induced p53, p21, and p27, and stopped cell proliferation (De-Castro Arce et al. 2007). The hepatitis C virus core protein inhibited cell growth by suppressing RARβ2 via DNA methylation in hepatocellular carcinoma (Lee et al. 2013). Latent membrane protein 1, an Epstein-Barr virus (EBV) oncogene product, induced hypermethylation of RARβ2 and EBV-mediated tumorigenesis in nasopharyngeal carcinoma (Seo et al. 2008). Hepatitis B virus X protein-induced hypermethylation of RARβ2 and suppressed RA-induced cell growth (Jung et al. 2010). HCV, EBV, and HBV, but not necessarily HPVs, produced oncogenic effects via epigenetic modification of RARβ2. Further studies on the relationship between viral infection and RARβ as well as RAR are needed to shed more light on this interesting topic.

Epigenetic modification of RAR also has implications for mental function and development. Neonatal maternal separation in rats weakened adult hippocampal neural differentiation by decreasing RAR alpha via methylation of its promoter (Boku et al. 2015). Vitamin A deficiency induced learning and memory impairment in rats by decreasing RAR alpha via suppression of H3 and H4 histone acetylation (Hou et al. 2015). Mature retinal ganglion cells in rats, considered to be irreplaceable, could exert a neuritogenic (regenerative) effect on optic axons by inducing RARβ via nitrosylation of histone deacetylase (HDAC) 2 and the acetylation of histone H3 (Koriyama et al. 2013). RAR was also found to preserve the stemness of adult tendon stem cells (TSCs) during expansion in vitro by histone methylation (Webb et al. 2016).

The epigenetic modifications of RAR are intimately associated with the pathogenesis of various diseases. Up to now the study of RAR epigenetic modification has focused mainly on DNA methylation and histone acetylation and has been led chiefly by oncologists. In the future, many other types of epigenetic modifications will undoubtedly come to light and improve our understanding of RAR, thereby also creating promising diagnostic and therapeutic applications.

Dictionary of Terms

  • Vitamin A – The name of a group of fat-soluble retinoids. Vitamin A supports cell growth and differentiation, playing a critical role in the normal formation and maintenance of the heart, lungs, kidneys, and other organs.

  • The retinoic acid receptor (RAR) – A type of nuclear receptor which can also act as a transcription factor that is activated by both all-trans retinoic acid and 9-cis retinoic acid.

  • Angiogenesis – The physiological process through which new blood vessels form from preexisting vessels. Angiogenesis is a normal and vital process in growth and development, as well as in wound healing but the angiogenesis inhibitors are used in the treatment of cancer.

  • Oncogene – a gene with the ability to cause a normal cell to become cancerous

  • Tumor suppressor gene – a gene that inhibits uncontrolled cell proliferation in normal cells. When this gene becomes inactivated, the cell is at increased risk of malignant proliferation.

Key Facts

  1. 1.

    Vitamin A is necessary for the body’s growth and health.

     
  2. 2.

    Vitamin A is especially important for the maintenance of vision, skin health, normal cognition, the formation of sperm, and the prevention of malignancies.

     
  3. 3.

    Vitamin A is converted to retinoids, which perform various important functions.

     
  4. 4.

    Retinoic acid, a type of retinoid, binds to the retinoic acid receptor (RAR).

     
  5. 5.

    RARβ2, a type of RAR, works as a tumor suppressor gene to prevent cancer progression.

     
  6. 6.

    RARβ2 is lost in most cancers by epigenetic modification.

     
  7. 7.

    If the epigenetic modification is reversed, RARβ2 is reexpressed and suppresses tumorigenesis and tumor progression.

     

Summary Points

  1. 1.

    Dietary vitamin A is converted to retinoids including retinal, retinol, and retinoic acid, in the metabolic pathway.

     
  2. 2.

    Two types of retinoic acid exist in the cell nucleus along with two types of receptor, the retinoic acid receptor (RAR) and retinoic X receptor (RXR). Each of these receptors has three subtypes, α, β, and γ.

     
  3. 3.

    Retinoic acid receptors are involved in a wide variety of functions including mediating tissue growth, blood vessel formation, the emotional and cognitive functions, and tumor suppression.

     
  4. 4.

    Retinoic acid is involved in cell differentiation. However, RARβ, a tumor suppressor gene, is epigenetically suppressed in most cancers.

     
  5. 5.

    Epigenetic modification of RAR in many cancers includes DNA methylation and histone hypoacetylation.

     
  6. 6.

    Histone deacetylase inhibitor and RA restore RAR expression and have shown a strong antitumor effect.

     
  7. 7.

    Some studies have suggested that RAR is regulated epigenetically in concert with other genes.

     
  8. 8.

    The relationship between viral infections and RARβ2 is complicated.

     
  9. 9.

    Epigenetic modification of RAR has implications for mental function and development.

     
  10. 10.

    The epigenetic modification of RAR could have clinical applications such as in diagnosing malignancies.

     
  11. 11.

    In the future, as many other types of epigenetic modifications become better understood, we can expect their diagnostic and therapeutic applications to be greatly expanded.

     

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of DermatologyTokyo Medical University Hachioji Medical CenterTokyoJapan

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