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Review
. 2014 Jul-Aug;20(4):467-84.
doi: 10.1093/humupd/dmu002. Epub 2014 Mar 14.

The dynamics of nuclear receptors and nuclear receptor coregulators in the pathogenesis of endometriosis

Sang Jun Han  1 , Bert W O'Malley  2
Affiliations
Review

The dynamics of nuclear receptors and nuclear receptor coregulators in the pathogenesis of endometriosis

Sang Jun Han et al. Hum Reprod Update. 2014 Jul-Aug.

Abstract

Background: Endometriosis is defined as the colonization and growth of endometrial tissue at anatomic sites outside the uterine cavity. Up to 15% of reproductive-aged women in the USA suffer from painful symptoms of endometriosis, such as infertility, pelvic pain, menstrual cycle abnormalities and increased risk of certain cancers. However, many of the current clinical treatments for endometriosis are not sufficiently effective and yield unacceptable side effects. There is clearly an urgent need to identify new molecular mechanisms that critically underpin the initiation and progression of endometriosis in order to develop more specific and effective therapeutics which lack the side effects of current therapies. The aim of this review is to discuss how nuclear receptors (NRs) and their coregulators promote the progression of endometriosis. Understanding the pathogenic molecular mechanisms for the genesis and maintenance of endometriosis as modulated by NRs and coregulators can reveal new therapeutic targets for alternative endometriosis treatments.

Methods: This review was prepared using published gene expression microarray data sets obtained from patients with endometriosis and published literature on NRs and their coregulators that deal with endometriosis progression. Using the above observations, our current understanding of how NRs and NR coregulators are involved in the progression of endometriosis is summarized.

Results: Aberrant levels of NRs and NR coregulators in ectopic endometriosis lesions are associated with the progression of endometriosis. As an example, endometriotic cell-specific alterations in gene expression are correlated with a differential methylation status of the genome compared with the normal endometrium. These differential epigenetic regulations can generate favorable cell-specific NR and coregulator milieus for endometriosis progression. Genetic alterations, such as single nucleotide polymorphisms and insertion/deletion polymorphisms of NR and coregulator genes, are frequently detected in ectopic lesions compared with the normal endometrium. These genetic variations impart new molecular properties to NRs and coregulators to increase their capacity to stimulate progression of endometriosis. Finally, post-translational modifications of NR coregulators, such as proteolytic processing, generate endometriosis-specific isoforms. Compared with the unmodified coregulators, these coregulator isoforms have unique functions that enhance the pathogenesis of endometriosis.

Conclusions: Epigenetic/genetic variations and posttranslational modifications of NRs and coregulators alter their original function so that they become potent 'drivers' of endometriosis progression.

Keywords: endometriosis; nuclear receptor; nuclear receptor coregulator.

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Figures

Figure 1
Figure 1
Epigenetic and genetic variation involved in the progression of endometriosis. (1) Epigenetic variation: the endometriotic tissues have aberrant levels of DNA methyltransferase (DNMT)s and polymorphism of DNMT3L compared with the normal endometrium. The alternation of DNMTs might be associated with hypermethylation of the SF-1 gene to enhance its expression in endometriotic tissues. The overexpression of SF-1 actively involves in estradiol production for the ectopic lesion proliferation. In contrast to SF-1, the alternation of DNMTs is correlated with hypomethylation of the estrogen receptor (ER)β gene to increase ERβ expression in endometriotic tissues. The increased ERβ binds to ERα promoter region to down-regulate ERα in endometriotic tissues. The reduced levels of ERα did not induce progesterone receptor (PR) gene expression in endometriotic tissue in response to estradiol. The alteration of DNMTs also may be directly involved in the hypomethylation of the PR gene promoter to down-regulate PR gene expression in endometriotic tissues. Therefore, both types of down-regulation of PR gene are associated with the development of progesterone resistance in endometriotic tissues. In addition to progesterone resistance, down-regulation of the PRB gene is associated with reduction of CRABP2 gene expression in endometriotic tissues to enhance pro-inflammatory signaling for survival of the ectopic lesion. (2) Genetic variation: the tumor protein 53 (TP53) PIN3 mutant, Arg72Pro TP53 mutant and deletion mutant of TP53 locus were frequently detected in endometriotic tissues. These TP53 mutations are correlated with the reduced levels of TP53 in endometriotic tissues. In addition, a PIN3 mutant can generate an RNA splicing mutant of TP53 lacking the N-terminal activation domain. Therefore, both types of alterations of TP53 induce proliferation activity of endometriotic tissues compared with wild-type endometrium. The +331G/A polymorphism of the PRB gene is correlated with the alteration of PRB gene expression in endometriotic tissues that might be associated with the development of progesterone resistance. (3) Unknown mechanism: estrogen receptor-related (ERR)-β, ERR-γ and PPAR-γ levels are reduced in endometriotic tissues compared with the normal endometrium, with an unknown mechanism preventing apoptosis signaling resulting in the survival of ectopic lesions. (Red triangles): increasing, (dark blue inverted triangles): decreasing, (red arrows): positive regulation and (green arrows): negative regulation.
Figure 2
Figure 2
Post-translational modification of NR coregulators in endometriotic tissues. (1) 20 kDa HSP70: in endometriotic tissue, SKI-1 protease actively processes HSP70 to the 20 kDa HSP70 isoform that does not bind I-kappa-B (IKB) protein. Therefore, V-Rel reticuloendotheliosis viral oncogene homolog A (RelA) and P50 easily are generated by the IκB kinase (IKK) complex activated by TNFα in endometriotic tissues. Therefore, RelA/P50 translocate into the nucleus to activate pro-survival gene expression in endometriotic cells. (2) 70 kDa steroid receptor coactivator (SRC)-1 isoform: in normal endometrial cells, TNFα activates caspase8/caspase3 cell death signaling to induce apoptosis (blue line). In endometriotic cells, however, TNFα-activated matrix metallopeptidase (MMP) 9 to proteolytically process the SRC-1 full-length protein to the 70 kDa SRC-1 C-terminal isoform (red line). The resulting 70 kDa SRC-1 isoform interacts with pro-caspase 8 to prevent its activation in response to TNFα. Therefore, inactivation of caspase 8 by the SRC-1 isoform effectively prevents apoptosis progression in ectopic lesions. In addition to anti-apoptosis, the SRC-1 isoform enhances gene expression involved in epithelial-to-mesenchymal transition (EMT) progression in ectopic lesions, supporting their survival.
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References

    1. Aghajanova L, Velarde MC, Giudice LC. The progesterone receptor coactivator Hic-5 is involved in the pathophysiology of endometriosis. Endocrinology. 2009;150:3863–3870. doi:10.1210/en.2009-0008. - DOI - PMC - PubMed
    1. Aghajanova L, Velarde MC, Giudice LC. Altered gene expression profiling in endometrium: evidence for progesterone resistance. Semin Reprod Med. 2010;28:51–58. doi:10.1055/s-0029-1242994. - DOI - PubMed
    1. Agic A, Xu H, Altgassen C, Noack F, Wolfler MM, Diedrich K, Friedrich M, Taylor RN, Hornung D. Relative expression of 1,25-dihydroxyvitamin D3 receptor, vitamin D 1 alpha-hydroxylase, vitamin D 24-hydroxylase, and vitamin D 25-hydroxylase in endometriosis and gynecologic cancers. Reprod Sci. 2007;14:486–497. doi:10.1177/1933719107304565. - DOI - PubMed
    1. Agic A, Djalali S, Diedrich K, Hornung D. Apoptosis in endometriosis. Gynecol Obstet Invest. 2009;68:217–223. doi:10.1159/000235871. - DOI - PubMed
    1. Al-Sabbagh M, Lam EWF, Brosens JJ. Mechanisms of endometrial progesterone resistance. Mol Cell Endocrinol. 2012;358:208–215. doi:10.1016/j.mce.2011.10.035. - DOI - PubMed

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