Elsevier

Advanced Drug Delivery Reviews

Volume 62, Issue 13, 30 October 2010, Pages 1227-1237
Advanced Drug Delivery Reviews

Nuclear receptor coregulators as a new paradigm for therapeutic targeting

https://doi.org/10.1016/j.addr.2010.09.016Get rights and content

Abstract

The complex function and regulation of nuclear receptors cannot be fully understood without a thorough knowledge of the receptor-associated coregulators that either enhance (coactivators) or inhibit (corepressors) transcription. While nuclear receptors themselves have garnered much attention as therapeutic targets, the clinical and etiological relevance of the coregulators to human diseases is increasingly recognized. Aberrant expression or function of coactivators and corepressors has been associated with malignant and metabolic disease development. Many of them are key epigenetic regulators and utilize enzymatic activities to modify chromatin through histone acetylation/deacetylation, histone methylation/demethylation or chromatin remodeling. In this review, we showcase and evaluate coregulators – such as SRCs and ANCCA – with the most promising therapeutic potential based on their physiological roles and involvement in various diseases that are revealed thus far. We also describe the structural features of the coactivator and corepressor functional domains and highlight areas that can be further explored for molecular targeting.

Introduction

The significance of understanding transcriptional regulation by the nuclear hormone receptors (NRs) is underscored by the diverse diseases, such as cancer, where numerous aberrations in hormone signaling pathways are uncovered. Transcriptional regulation by NRs involves ordered and dynamic protein-protein interactions between the receptor, associated coregulators, and the RNA polymerase II transcriptional machinery at the chromatin of target genes. Many coregulators possess enzymatic activities or recruit multi-subunit enzymatic protein complexes to mediate specific chromatin modifications that result in either transcriptional activation or repression (see below).

Coregulators can be divided into two general classes, namely, coactivators and corepressors. Coactivators are generally characterized by their ability to enhance NR transactivation by interacting with the N-terminus and/or the C-terminal ligand binding domain (LBD) of agonist-bound NRs. The counterparts of coactivators, called corepressors, were identified as mediators for selectively repressing NR-dependent gene transcription through interaction with unliganded or antagonist-bound (or in some cases, agonist-bound) NRs on their target genes [1].

Because many coregulators influence the activity of multiple nuclear hormone receptors and thus the transcriptional output of many gene networks, it is not surprising that disruption of their normal function or expression can contribute to a vast spectrum of physiological abnormalities and diseases. Many studies using mouse models support this notion and have contributed to our understanding of coregulators for normal biological function. For example, gene knockout studies have demonstrated important roles for individual members of the p160 family of coactivators (see below) in hormonal responses and organ developments during reproduction, metabolism, and growth [2]. Furthermore, the phenotypic defects were not restricted to hormone-regulated tissues and processes, reflecting in some circumstances a more general role played by the coregulators in control of gene expression. While we acknowledge that many coregulators associate with and mediate the functions of NRs besides steroid receptors, their aberrant expression and function appear to be best understood so far in the steroid hormone responsive human malignancies such as breast cancer and prostate cancer (e.g. the p160/SRC family) or metabolism and energy homeostasis (e.g. PGC-1). Here, we outline the structure and function of coregulators that can thus be considered as highly attractive and promising, new therapeutic targets (Fig. 1, Fig. 2).

Section snippets

Coactivators — structure, function and therapeutic implications

Enzymatic modification of chromatin structure is at the heart of gene regulation at the transcriptional level. Coactivators can promote gene-specific NR-mediated transcription via several activities. Changes in post-translational modifications on core histone tails – particularly acetylation and methylation – serve as a crucial step in the remodeling of chromatin structure during gene expression. Loss-of-function experiments revealed that the histone acetylase (HAT) activities of the general

NCoR and SMRT — repressors of unliganded and antagonist-bound NRs

The first NR corepressors were identified based on their ability to mediate transcriptional repression by unliganded thyroid hormone (TR) and retinoid acid receptors. The aptly named NR corepressor (NCoR) and silencing mediator for RAR and TR (SMRT) contain multiple repression domains that serve as docking platforms for recruitment of additional components in the corepressor complex including HDAC and mSin3. Later studies discovered that NCoR and SMRT can interact with additional NRs in the

Concluding remarks

Substantial research progress in NR coregulator function and mechanisms provided valuable insights into their contributions to disease development. This review focused on thus far relatively well-characterized representatives from both classes of coregulators and coincidentally, the evidence we present here attribute to their pathological and clinical relevance in various malignancies. However, as illustrated by the coactivator PGC-1α, some coregulators have established roles in physiological

Acknowledgments

This work was supported in part by NIH grants R01DK53528 (M.L. Privalsky), R01CA113860, R01CA134766 and R01DK060019 (H-W Chen), and DoD grant W81XWH-07-1-0312 (J. X Zou).

References (146)

  • H.-B. Zhou et al.

    Bicyclo[2.2.2]octanes: close structural mimics of the nuclear receptor-binding motif of steroid receptor coactivators

    Bioorganic & Medicinal Chemistry Letters

    (2007)
  • A.L. LaFrate et al.

    Synthesis and biological evaluation of guanylhydrazone coactivator binding inhibitors for the estrogen receptor

    Bioorganic & Medicinal Chemistry

    (2008)
  • L.H. Wang et al.

    Disruption of estrogen receptor DNA-binding domain and related intramolecular communication restores tamoxifen sensitivity in resistant breast cancer

    Cancer Cell

    (2006)
  • L.A. Arnold et al.

    Discovery of small molecule inhibitors of the interaction of the thyroid hormone receptor with transcriptional coregulators

    The Journal of Biological Chemistry

    (2005)
  • A.E. Wallberg et al.

    Coordination of p300-mediated chromatin remodeling and TRAP/mediator function through coactivator PGC-1a

    Molecular Cell

    (2003)
  • S. Li et al.

    Genome-wide coactivation analysis of PGC-1a identifies BAF60a as a regulator of hepatic lipid metabolism

    Cell Metabolism

    (2008)
  • P. Puigserver et al.

    A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis

    Cell

    (1998)
  • A. Hammarstedt et al.

    Reduced expression of PGC-1 and insulin-signaling molecules in adipose tissue is associated with insulin resistance

    Biochemical and Biophysical Research Communications

    (2003)
  • M. Lagouge et al.

    Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1a

    Cell

    (2006)
  • P. Palsamy et al.

    Resveratrol, a natural phytoalexin, normalizes hyperglycemia in streptozotocin-nicotinamide induced experimental diabetic rats

    Biomedicine & Pharmacotherapy

    (2008)
  • P. Palsamy et al.

    Modulatory effects of resveratrol on attenuating the key enzymes activities of carbohydrate metabolism in streptozotocin-nicotinamide-induced diabetic rats

    Chemico-Biological Interactions

    (2009)
  • M.A. Surani et al.

    Genetic and epigenetic regulators of pluripotency

    Cell

    (2007)
  • M. Collado et al.

    Cellular senescence in cancer and aging

    Cell

    (2007)
  • S.L. Foster et al.

    Gene-specific control of the TLR-induced inflammatory response

    Clinical Immunology

    (2009)
  • P.A. Jones et al.

    The Epigenomics of Cancer

    Cell

    (2007)
  • S.C. Kampranis et al.

    Chapter 4 histone demethylases and cancer

  • A.J. Bannister et al.

    Histone methylation: dynamic or static?

    Cell

    (2002)
  • Y. Shi et al.

    Histone demethylation mediated by the nuclear amine oxidase homolog LSD1

    Cell

    (2004)
  • Y.-J. Shi et al.

    Regulation of LSD1 histone demethylase activity by its associated factors

    Molecular Cell

    (2005)
  • T. Kouzarides

    Chromatin modifications and their function

    Cell

    (2007)
  • J.C. Eissenberg et al.

    Leaving a mark: the many footprints of the elongating RNA polymerase II

    Current Opinion in Genetics & Development

    (2006)
  • M.G. Lee et al.

    Histone H3 Lysine 4 demethylation is a target of nonselective antidepressive medications

    Chemistry & Biology

    (2006)
  • A. Scoumanne et al.

    The lysine-specific demethylase 1 is required for cell proliferation in both p53-dependent and -independent manners

    The Journal of Biological Chemistry

    (2007)
  • S. Shin et al.

    Activation of androgen receptor by histone demethylases JMJD2A and JMJD2D

    Biochemical and Biophysical Research Communications

    (2007)
  • K. Yamane et al.

    JHDM2A, a JmjC-Containing H3K9 Demethylase, Facilitates Transcription Activation by Androgen Receptor

    Cell

    (2006)
  • C.K. Glass et al.

    The coregulator exchange in transcriptional functions of nuclear receptors

    Genes & Development

    (2000)
  • J. Xu et al.

    Review of the in vivo functions of the p160 steroid receptor coactivator family

    Molecular Endocrinology

    (2003)
  • D.P. Edwards

    The role of coactivators and corepressors in the biology and mechanism of action of steroid hormone receptors

    Journal of Mammary Gland Biology and Neoplasia

    (2000)
  • P.J. Kushner

    Estrogen receptor action through target genes with classical and alternative response elements

    Pure and Applied Chemistry

    (2003)
  • R. Metivier et al.

    Synergism between ERa transactivation function 1 (AF-1) and AF-2 mediated by steroid receptor coactivator protein-1: requirement for the AF-1 a-helical core and for a direct interaction between the N- and C-terminal domains

    Molecular Endocrinology

    (2001)
  • E.M. McInerney et al.

    Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation

    Genes & Development

    (1998)
  • B.D. Darimont et al.

    Structure and specificity of nuclear receptor–coactivator interactions

    Genes & Development

    (1998)
  • M. Doi, J. Hirayama, P. Sassone-Corsi, Circadian Regulator CLOCK Is a Histone Acetyltransferase, Cell 125 (2006)...
  • J.-M. Wurtz et al.

    A canonical structure for the ligand-binding domain of nuclear receptors

    Nature Structural & Molecular Biology

    (1996)
  • J.M. Hall et al.

    Allosteric regulation of estrogen receptor structure, function, and coactivator recruitment by different estrogen response elements

    Molecular Endocrinology

    (2002)
  • M. Harigopal et al.

    Estrogen receptor co-activator (AIB1) protein expression by automated quantitative analysis (AQUA) in a breast cancer tissue microarray and association with patient outcome

    Breast Cancer Research and Treatment

    (2009)
  • L. Dihge et al.

    Epidermal growth factor receptor (EGFR) and the estrogen receptor modulator amplified in breast cancer (AIB1) for predicting clinical outcome after adjuvant tamoxifen in breast cancer

    Breast Cancer Research and Treatment

    (2008)
  • E. Myers et al.

    Associations and interactions between Ets-1 and Ets-2 and coregulatory proteins, SRC-1, AIB1, and NCoR in breast cancer

    Clinical Cancer Research

    (2005)
  • F.J. Fleming et al.

    Expression of SRC-1, AIB1, and PEA3 in HER2 mediated endocrine resistant breast cancer; a predictive role for SRC-1

    Journal of Clinical Pathology

    (2004)
  • C.K. Osborne et al.

    Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer

    Journal of the National Cancer Institute

    (2003)
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