Nuclear Receptor Coactivators: Master Regulators of Human Health and Disease

Dasgupta, Subhamoy; Lonard, David M.; O’Malley, Bert W.

doi:10.1146/annurev-med-051812-145316

Cited by 186 publications

(164 citation statements)

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“…Although the molecular mechanisms underlying prostate cancer progression to lethal hormone refractory prostate cancer (HRPC) [9][10][11][12][13] are incompletely understood, activation of downstream signals by hypersensitive or overexpressed ARs is considered to be important. The epigenetic status of prostate cancer cells is modulated by AR binding and the subsequent recruitment of co-activators or co-repressors [14][15][16][17][18] . Acetylation, methylation, phosphorylation, ubiquitylation and ADP ribosylation of histones critically affect transcriptional regulation by ARs [19][20][21] .…”

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confidence: 99%

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

et al. 2015

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Modulation of epigenetic patterns has promising efficacy for treating cancer. 5-Hydroxymethylated cytosine (5-hmC) is an epigenetic mark potentially important in cancer. Here we report that 5-hmC is an epigenetic hallmark of prostate cancer (PCa) progression. A member of the ten-eleven translocation (TET) proteins, which catalyse the oxidation of methylated cytosine (5-mC) to 5-hmC, TET2, is repressed by androgens in PCa. Androgen receptor (AR)-mediated induction of the miR-29 family, which targets TET2, are markedly enhanced in hormone refractory PCa (HRPC) and its high expression predicts poor outcome of PCa patients. Furthermore, decreased expression of miR-29b results in reduced tumour growth and increased TET2 expression in an animal model of HRPC. Interestingly, global 5-hmC modification regulated by miR-29b represses FOXA1 activity. A reduction in 5-hmC activates PCa-related key pathways such as mTOR and AR. Thus, DNA modification directly links the TET2-dependent epigenetic pathway regulated by AR to 5-hmC-mediated tumour progression.

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confidence: 99%

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

et al. 2015

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“…A distinct requirement or competition for co-activators has been proposed to offer a potential explanation for how LXRs and other members of the nuclear receptor family can differentially regulate their target genes (42). It is therefore possible that HBX41-108 affects a unique transcriptional co-factor used by LXRs to control IDOL expression.…”

Section: Resultsmentioning

confidence: 99%

Deubiquitylase Inhibition Reveals Liver X Receptor-independent Transcriptional Regulation of the E3 Ubiquitin Ligase IDOL and Lipoprotein Uptake

Nelson

Cook

Loregger

et al. 2016

Journal of Biological Chemistry

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Cholesterol metabolism is subject to complex transcriptional and nontranscriptional regulation. Herein, the role of ubiquitylation is emerging as an important post-translational modification that regulates cholesterol synthesis and uptake. Similar to other post-translational modifications, ubiquitylation is reversible in a process dependent on activity of deubiquitylating enzymes (DUBs). Yet whether these play a role in cholesterol metabolism is largely unknown. As a first step to test this possibility, we used pharmacological inhibition of cellular DUB activity. Short term (2 h) inhibition of DUBs resulted in accumulation of high molecular weight ubiquitylated proteins. This was accompanied by a dramatic decrease in abundance of the LDLR and attenuated LDL uptake into hepatic cells. Importantly, this occurred in the absence of changes in the mRNA levels of the LDLR or other SREBP2-regulated genes, in line with this phenotype being a post-transcriptional event. Mechanistically, we identify transcriptional induction of the E3 ubiquitin ligase IDOL in human and rodent cells as the underlying cause for ubiquitylation-dependent lysosomal degradation of the LDLR following DUB inhibition. In contrast to the established transcriptional regulation of IDOL by the sterol-responsive liver X receptor (LXR) transcription factors, induction of IDOL by DUB inhibition is LXR-independent and occurs in Lxr␣␤ ؊/؊ MEFs.Consistent with the role of DUBs in transcriptional regulation, we identified a 70-bp region in the proximal promoter of IDOL, distinct from that containing the LXR-responsive element, which mediates the response to DUB inhibition. In conclusion, we identify a sterol-independent mechanism to regulate IDOL expression and IDOL-mediated lipoprotein receptor degradation.Elevated levels of plasma LDL represent a major risk factor for development of atherosclerosis and cardiovascular disease (1). Because of its ability to promote LDL uptake into cells, the LDL receptor (LDLR) 2 is a major determinant of plasma LDL levels (2). The pivotal role of the LDLR in LDL metabolism is exemplified by the fact that LDLR mutations account for most incidences of familial hypercholesterolemia, a disease characterized by reduced hepatic LDL clearance, elevated plasma cholesterol levels, and accelerated cardiovascular disease (1, 3).The LDLR is subject to tight transcriptional and post-transcriptional regulation, which is largely governed by the intracellular levels of cholesterol (4). At the level of transcription, these pathways are regulated by two nuclear transcription factor families: SREBP1 and SREBP2 (5-7), and the liver X receptor ␣ and ␤ (LXRs) (8, 9). When cellular sterol levels decline, SREBPs are activated to induce genes required for de novo cholesterol biosynthesis, as well as the LDLR to increase uptake of LDL cholesterol (4). In contrast, when sterol levels rise, LXRs become activated by their endogenous ligands. These ligands include oxidized cholesterol derivatives (oxysterols) and intermediates of the cholesterol synthes...

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“…1 Targeting p160/SRC co-activators of the androgen receptor Steroid hormone receptor signaling is dependent on a number of transcriptional co-activators that enhance binding of the receptor to chromatin and promote the transcriptional activation of target genes. 2 Not surprisingly, such co-activators have been found to be upregulated in prostate cancer development and progression, where they promote AR signaling in general, but more specifically sustain activation of the AR under low availability of androgens as encountered in castration-resistant disease. 2,3 One family of classical AR co-activators includes the p160/SRC family (NCOA1, NCOA2, and NCOA3).…”

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confidence: 99%

“…2 Not surprisingly, such co-activators have been found to be upregulated in prostate cancer development and progression, where they promote AR signaling in general, but more specifically sustain activation of the AR under low availability of androgens as encountered in castration-resistant disease. 2,3 One family of classical AR co-activators includes the p160/SRC family (NCOA1, NCOA2, and NCOA3). At the molecular level, these co-activators harbor LXXLL motifs that enable binding to the ligand-bound steroid receptor.…”

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confidence: 99%

“…Their conserved C-terminal activation domains engage transcriptional activation of target genes by mediating chromatin acetylation by CBP and p300. 2 Recent drug discovery efforts have revealed tool compounds targeting the p160/SRC co-activators. For example, a high throughput screening effort identified a small molecule inhibitor for NCOA1 and NCOA3, which promoted NCOA3 protein degradation and was able to block cancer cell growth.…”

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confidence: 99%

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