Repression of Runx2 by Androgen Receptor (AR) in Osteoblasts and Prostate Cancer Cells: AR Binds Runx2 and Abrogates Its Recruitment to DNA

Baniwal, Sanjeev K.; Khalid, Omar; Sir, Donna; Buchanan, Grant; Coetzee, Gerhard A.; Frenkel, Baruch

doi:10.1210/me.2008-0470

Cited by 63 publications

(79 citation statements)

References 81 publications

(108 reference statements)

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“…5). Because sex steroids inhibit Runx2 activity [24, 25], they likely attenuate bone turnover in part by counteracting some of the Runx2-mediated osteoclastogenic mechanisms suggested by the microarray data. The assignment of both osteoblast differentiation [1, 2] and osteoblast-driven osteoclastogenesis [7–9] to Runx2 likely contributes to the coupling of bone formation and resorption.…”

Section: Resultsmentioning

confidence: 99%

“…Despite the importance of Runx2 in skeletal development and bone turnover, and the likely roles of Runx2 in interpreting signals from extracellular matrix proteins [17], TGFβ and BMPs [18, 19], Wnts [20], PTH [21], glucocorticoids [22], and sex steroids [10, 23–25], little is known about gene networks regulated by Runx2 in osteoblasts. Most microarray-based gene expression profiling of osteoblast differentiation did not specifically focus on Runx2 [26–30].…”

Section: Introductionmentioning

confidence: 99%

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Runx2 promotes both osteoblastogenesis and novel osteoclastogenic signals in ST2 mesenchymal progenitor cells

et al. 2011

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Summary We profiled the global gene expression of a bone marrow-derived mesenchymal pluripotent cell line in response to Runx2 expression. Besides osteoblast differentiation, Runx2 promoted the osteoclastogenesis of co-cultured splenocytes. This was attributable to the upregulation of many novel osteoclastogenic genes and the downregulation of anti-osteoclastogenic genes. Introduction In addition to being a master regulator for osteoblast differentiation, Runx2 controls osteoblast-driven osteoclastogenesis. Previous studies profiling gene expression during osteoblast differentiation had limited focus on Runx2 or paid little attention to its role in mediating osteoblast-driven osteoclastogenesis. Methods ST2/Rx2dox, a bone marrow-derived mesenchymal pluripotent cell line that expresses Runx2 in response to Doxycycline (Dox), was used to profile Runx2-induced gene expression changes. Runx2-induced osteoblast differentiation was assessed based on alkaline phosphatase staining and expression of classical marker genes. Osteoclastogenic potential was evaluated by TRAP staining of osteoclasts that differentiated from primary murine splenocytes co-cultured with the ST2/Rx2dox cells. The BeadChip™ platform (Illumina) was used to interrogate genome-wide expression changes in ST2/Rx2dox cultures after treatment with Dox or vehicle for 24 or 48 h. Expression of selected genes was also measured by RT-qPCR. Results Dox-mediated Runx2 induction in ST2 cells stimulated their own differentiation along the osteoblast lineage and the differentiation of co-cultured splenocytes into osteoclasts. The latter was attributable to the stimulation of osteoclastogenic genes such as Sema7a, Ltc4s, Efnb1, Apcdd1, and Tnc as well as the inhibition of anti-osteoclastogenic genes such as Tnfrsf11b (OPG), Sema3a, Slco2b1, Ogn, Clec2d (Ocil), Il1rn, and Rspo2. Conclusion Direct control of osteoblast differentiation and concomitant indirect control of osteoclast differentiation, both through the activity of Runx2 in pre-osteoblasts, constitute a novel mechanism of coordination with a potential crucial role in coupling bone formation and resorption.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Runx2 promotes both osteoblastogenesis and novel osteoclastogenic signals in ST2 mesenchymal progenitor cells

et al. 2011

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“…Their reexpression during androgen ablation therapy is thought to contribute to disease regression, and they may become repressed once again in CRPC. Despite this importance, only a few studies have reported AR inhibition of a handful of genes (Grosse et al 2011), a majority of which, however, suggested indirect mechanisms involving inhibition of cofactor proteins with transactivating functions such as SP1 (Verras et al 2007;Liu et al 2008;Baniwal et al 2009;Song et al 2010). Few of them, indeed, suggested direct AR binding to DNA, however, often through an altered DNA binding specificity (Lanzino et al 2010;Qi et al 2011).…”

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confidence: 99%

Cooperation between Polycomb and androgen receptor during oncogenic transformation

Zhao¹,

Yu²,

Runkle³

et al. 2011

Genome Res.

116

121

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Androgen receptor (AR) is a hormone-activated transcription factor that plays important roles in prostate development and function, as well as malignant transformation. The downstream pathways of AR, however, are incompletely understood. AR has been primarily known as a transcriptional activator inducing prostate-specific gene expression. Through integrative analysis of genome-wide AR occupancy and androgen-regulated gene expression, here we report AR as a globally acting transcriptional repressor. This repression is mediated by androgen-responsive elements (ARE) and dictated by Polycomb group protein EZH2 and repressive chromatin remodeling. In embryonic stem cells, AR-repressed genes are occupied by EZH2 and harbor bivalent H3K4me3 and H3K27me3 modifications that are characteristic of differentiation regulators, the silencing of which maintains the undifferentiated state. Concordantly, these genes are silenced in castration-resistant prostate cancer rendering a stem cell–like lack of differentiation and tumor progression. Collectively, our data reveal an unexpected role of AR as a transcriptional repressor inhibiting non-prostatic differentiation and, upon excessive signaling, resulting in cancerous dedifferentiation.

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“…The genetic interaction of the AML1-ETO and nuclear receptors is consistent with the known associations of human vitamin D, androgen and estrogen nuclear receptors, and Runx proteins in modulating their transcriptional activity. [40][41][42] AML1-ETO and nuclear receptor complexes can also interact through corepressor proteins, such as NcoR/SMRT, HDACs, and Sin3A. It is well known that deregulation in retinoid acid signaling or vitamin D signaling contribute to pathogenesis of leukemia in humans.…”

Section: Discussionmentioning

confidence: 99%

Genetic manipulation of AML1-ETO–induced expansion of hematopoietic precursors in a Drosophila model

Sinenko

Hung

Moroz

et al. 2010

Blood

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Among mutations in human Runx1/AML1 transcription factors, the t(8;21)(q22;q22) genomic translocation that creates an AML1-ETO fusion protein is implicated in etiology of the acute myeloid leukemia. To identify genes and components associated with this oncogene we used Drosophila as a genetic model. Expression of AML1-ETO caused an expansion of hematopoietic precursors in Drosophila, which expressed high levels of reactive oxygen species (ROS). Mutations in functional domains of the fusion protein suppress the proliferative phenotype. In a genetic screen, we found that inactivation of IntroductionRUNX genes encode highly conserved Runt domain transcription factors (AML/RUNX proteins), which play critical roles during blood cell development in metazoan species. [1][2][3][4] Mutations that disrupt the activity of AML1/Runx1 lead to hematopoietic disorders including myelodysplastic syndrome and acute myeloid leukemia (AML). 2,5 AML is the most frequent and debilitating form of leukemia with approximately a quarter million new cases diagnosed each year worldwide. The t(8;21) (q22;q22) chromosomal translocation that creates the AML1-ETO fusion product is present in 12%-15% of all cases of AML patients. The M2 subtype of AML carrying the AML1-ETO fusion protein is characterized by excessive production of granulocyte precursors. 6 Under normal conditions, AML1/RUNX1 (also known as core binding factor-␣, CBF␣) in association with CBF␤ binds the enhancer core sequence, TGT/CGGT, to activate tissue-specific expression of a number of hematopoietic genes. 4 ETO (also known as MTG8) functions as a transcriptional repressor by recruiting a protein complex consisting of histone deacetylases (HDACs), the nuclear receptor co-receptor (N-CoR), mSin3A and the silencing mediator of retinoid and thyroid hormone receptor (SMRT). 7 ETO function has been implicated in the Notch pathway, 8 and it interacts with SON and TCF4. 9,10 The (8,21)(q22;q22) chromosomal aberration produces a potent oncogenic fusion protein consisting of most of the Runt domain of AML1 and nearly the complete sequence of ETO. 11 The general view among investigators in the field is that the AML1-ETO fusion product acts as a constitutive repressor form of AML1. 12,13 It has also been shown that this fusion protein has other activities in addition to interfering with AML1 function. 14,15 For example, AML1-ETO knock-in mouse embryos contain highly proliferative multilineage hematopoietic progenitors that are not found when either AML1 or CBF␤ is disrupted. 12,14 Evidently, the full range of AML1-ETO target genes as well as components involved in the pathway, and their relevance to AML pathogenesis is not completely understood.To further our understanding of AML pathogenesis, additional animal models that allow in vivo genetic analysis are needed to complement studies in the existing mouse models. To this end, a Drosophila model is valuable due to the availability of facile genetic screens, a nearly complete collection of mutants, and advanced genetic technologies. T...

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Repression of Runx2 by Androgen Receptor (AR) in Osteoblasts and Prostate Cancer Cells: AR Binds Runx2 and Abrogates Its Recruitment to DNA

Cited by 63 publications

References 81 publications

Runx2 promotes both osteoblastogenesis and novel osteoclastogenic signals in ST2 mesenchymal progenitor cells

Runx2 promotes both osteoblastogenesis and novel osteoclastogenic signals in ST2 mesenchymal progenitor cells

Cooperation between Polycomb and androgen receptor during oncogenic transformation

Genetic manipulation of AML1-ETO–induced expansion of hematopoietic precursors in a Drosophila model

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