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NR4A1; nuclear receptor subfamily 4, group A, member 1 (12q13)

Gene Summary

Gene:NR4A1; nuclear receptor subfamily 4, group A, member 1
Aliases: HMR, N10, TR3, NP10, GFRP1, NAK-1, NGFIB, NUR77
Location:12q13
Summary:This gene encodes a member of the steroid-thyroid hormone-retinoid receptor superfamily. Expression is induced by phytohemagglutinin in human lymphocytes and by serum stimulation of arrested fibroblasts. The encoded protein acts as a nuclear transcription factor. Translocation of the protein from the nucleus to mitochondria induces apoptosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:nuclear receptor subfamily 4 group A member 1
HPRD
Source:NCBI
Updated:11 December, 2014

Gene
Ontology:

What does this gene/protein do?
Show (28)

Pathways:

What pathways are this gene/protein implicaed in?
- MAPK signaling pathway KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 11 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Receptors, Cytoplasmic and Nuclear
  • Retinoic Acid
  • Indoles
  • Oligonucleotide Array Sequence Analysis
  • Virus Integration
  • Protein Binding
  • Neoplasm Proteins
  • RTPCR
  • Cancer Gene Expression Regulation
  • DNA-Binding Proteins
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Transcription Factors
  • Receptors, Thyroid Hormone
  • Gene Expression
  • Transcriptional Activation
  • Apoptosis
  • Antineoplastic Agents
  • Cell Survival
  • Cell Proliferation
  • Translocation
  • Cervical Cancer
  • Signal Transduction
  • Nerve Tissue Proteins
  • Chromosomes, Human, Pair None
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Receptors, Steroid
  • Messenger RNA
  • Breast Cancer
  • Nuclear Proteins
  • Colonic Neoplasms
  • Knockout Mice
  • RNA Interference
  • Young Adult
  • Western Blotting
  • Gene Expression Profiling
  • Gene Knockdown Techniques
  • Promoter Regions
  • Base Sequence
  • Transcription
  • BCL2
Tag cloud generated 11 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (3)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Cervical CancerNR4A1 and Cervical Cancer View Publications1
Breast CancerNR4A1 and Breast Cancer View Publications7
Colorectal CancerNR4A1 and Colonic Neoplasms View Publications7

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: NR4A1 (cancer-related)

Agren R, Mardinoglu A, Asplund A, et al.
Identification of anticancer drugs for hepatocellular carcinoma through personalized genome-scale metabolic modeling.
Mol Syst Biol. 2014; 10:721 [PubMed] Free Access to Full Article Related Publications
Genome-scale metabolic models (GEMs) have proven useful as scaffolds for the integration of omics data for understanding the genotype-phenotype relationship in a mechanistic manner. Here, we evaluated the presence/absence of proteins encoded by 15,841 genes in 27 hepatocellular carcinoma (HCC) patients using immunohistochemistry. We used this information to reconstruct personalized GEMs for six HCC patients based on the proteomics data, HMR 2.0, and a task-driven model reconstruction algorithm (tINIT). The personalized GEMs were employed to identify anticancer drugs using the concept of antimetabolites; i.e., drugs that are structural analogs to metabolites. The toxicity of each antimetabolite was predicted by assessing the in silico functionality of 83 healthy cell type-specific GEMs, which were also reconstructed with the tINIT algorithm. We predicted 101 antimetabolites that could be effective in preventing tumor growth in all HCC patients, and 46 antimetabolites which were specific to individual patients. Twenty-two of the 101 predicted antimetabolites have already been used in different cancer treatment strategies, while the remaining antimetabolites represent new potential drugs. Finally, one of the identified targets was validated experimentally, and it was confirmed to attenuate growth of the HepG2 cell line.

Related: Liver Cancer


Deutsch AJ, Rinner B, Wenzl K, et al.
NR4A1-mediated apoptosis suppresses lymphomagenesis and is associated with a favorable cancer-specific survival in patients with aggressive B-cell lymphomas.
Blood. 2014; 123(15):2367-77 [PubMed] Related Publications
NR4A1 (Nur77) and NR4A3 (Nor-1) function as tumor suppressor genes as demonstrated by the rapid development of acute myeloid leukemia in the NR4A1 and NR4A3 knockout mouse. The aim of our study was to investigate NR4A1 and NR4A3 expression and function in lymphoid malignancies. We found a vastly reduced expression of NR4A1 and NR4A3 in chronic lymphocytic B-cell leukemia (71%), in follicular lymphoma (FL, 70%), and in diffuse large B-cell lymphoma (DLBCL, 74%). In aggressive lymphomas (DLBCL and FL grade 3), low NR4A1 expression was significantly associated with a non-germinal center B-cell subtype and with poor overall survival. To investigate the function of NR4A1 in lymphomas, we overexpressed NR4A1 in several lymphoma cell lines. Overexpression of NR4A1 led to a higher proportion of lymphoma cells undergoing apoptosis. To test the tumor suppressor function of NR4A1 in vivo, the stable lentiviral-transduced SuDHL4 lymphoma cell line harboring an inducible NR4A1 construct was further investigated in xenografts. Induction of NR4A1 abrogated tumor growth in the NSG mice, in contrast to vector controls, which formed massive tumors. Our data suggest that NR4A1 has proapoptotic functions in aggressive lymphoma cells and define NR4A1 as a novel gene with tumor suppressor properties involved in lymphomagenesis.

Related: Apoptosis


To SK, Zeng WJ, Zeng JZ, Wong AS
Hypoxia triggers a Nur77-β-catenin feed-forward loop to promote the invasive growth of colon cancer cells.
Br J Cancer. 2014; 110(4):935-45 [PubMed] Article available free on PMC after 18/02/2015 Related Publications
BACKGROUND: β-Catenin is a potent oncogenic protein in colorectal cancer (CRC), but the targets and regulation of this important signalling molecule are not completely understood. Hypoxia is a prominent feature of solid tumours that contributes to cancer progression.
METHODS: Here, we analysed the regulation between Nur77 and β-catenin under hypoxic conditions. Cell proliferation, migration, and invasion assays were performed to assess functional consequences.
RESULTS: We showed that hypoxia stimulated co-upregulation of β-catenin and Nur77 in a number of human CRC cell lines. Interestingly, expression of β-catenin and Nur77 by hypoxia formed a mutual feedback regulation circuits that conferred aggressive growth of CRC. Overexpression of β-catenin increased Nur77 transcription through hypoxia-inducible factor-1α rather than T-cell factor. Nur77-mediated activation of β-catenin by hypoxia was independent of both DNA binding and transactivation. Further, we showed that hypoxic activation of β-catenin was independent of the classical adenomatous polyposis coli and p53 pathways, but stimulated by phosphatidylinositol 3-kinase/Akt in a Nur77-dependent manner. Under hypoxic conditions, enhanced β-catenin and Nur77 expression synergistically stimulated CRC cell migration, invasion, and epithelial-mesenchymal transition.
CONCLUSION: These findings provide a novel molecular mechanism for hypoxic CRCs that may contribute to tumour progression, and its targeting may represent an effective therapeutic avenue.

Related: HIF1A AKT1 Signal Transduction TP53 CTNNB1 gene


Cheng W, Su Y, Xu F
CHD1L: a novel oncogene.
Mol Cancer. 2013; 12(1):170 [PubMed] Article available free on PMC after 18/02/2015 Related Publications
Comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer and  - 140 driver genes have been identified, but not all of them have been extensively investigated. CHD1L (chromodomain helicase/ATPase DNA binding protein 1-like gene) or ALC1 (amplified in liver cancer 1) is a newly identified oncogene located at Chr1q21 and it is amplified in many solid tumors. Functional studies of CHD1L in hepatocellular carcinoma and other tumors strongly suggested that its oncogenic role in tumorigenesis is through unleashed cell proliferation, G1/S transition and inhibition of apoptosis. The underlying mechanisms of CHD1L activation may disrupt the cell death program via binding the apoptotic protein Nur77 or through activation of the AKT pathway by up-regulation of CHD1L-mediated target genes (e.g., ARHGEF9, SPOCK1 or TCTP). CHD1L is now considered to be a novel independent biomarker for progression, prognosis and survival in several solid tumors. The accumulated knowledge about its functions will provide a focus to search for targeted treatment in specific subtypes of tumors.

Related: Cancer Prevention and Risk Reduction


Wu J, Liu J, Jia R, Song H
Nur77 inhibits androgen-induced bladder cancer growth.
Cancer Invest. 2013; 31(10):654-60 [PubMed] Related Publications
Currently, bladder cancer ranks as the second most common genitourinary malignancy which is exacting significant morbidity and mortality worldwide. Although there are abundant epidemiological and basic studies which strongly suggest the role of androgen hormone in bladder cancer, the underlying mechanism is not fully understood. In the current study, we sought to identify a new competitive inhibitor for androgen receptor in bladder cancer cells. Our results showed that Nur77 hyperexpression inhibits UM-UC-3 cell growth and cell cycle progression while Nur77 knockdown exerts the opposite effect. In our cell culture model, we also demonstrated that Nur77 competitively inhibits androgen-dependent transcription activity and more specifically, Nur77 competes with androgen receptor for binding to src-1, a well-known coactivator for steroids. More importantly, we also showed that a small molecule agonist for Nur77, Cytosporone B, significantly inhibits androgen-dependent bladder cancer cell growth in two different cell lines. These data provide a good proof-of-principle that Nur77 signaling machinery could be a new target for growth control of androgen-dependent bladder cancer cells.

Related: Signal Transduction Bladder Cancer Bladder Cancer - Molecular Biology


Johannessen CM, Johnson LA, Piccioni F, et al.
A melanocyte lineage program confers resistance to MAP kinase pathway inhibition.
Nature. 2013; 504(7478):138-42 [PubMed] Article available free on PMC after 18/02/2015 Related Publications
Malignant melanomas harbouring point mutations (Val600Glu) in the serine/threonine-protein kinase BRAF (BRAF(V600E)) depend on RAF-MEK-ERK signalling for tumour cell growth. RAF and MEK inhibitors show remarkable clinical efficacy in BRAF(V600E) melanoma; however, resistance to these agents remains a formidable challenge. Global characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. Here we carried out systematic gain-of-function resistance studies by expressing more than 15,500 genes individually in a BRAF(V600E) melanoma cell line treated with RAF, MEK, ERK or combined RAF-MEK inhibitors. These studies revealed a cyclic-AMP-dependent melanocytic signalling network not previously associated with drug resistance, including G-protein-coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). Preliminary analysis of biopsies from BRAF(V600E) melanoma patients revealed that phosphorylated (active) CREB was suppressed by RAF-MEK inhibition but restored in relapsing tumours. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS, NR4A1, NR4A2 and MITF. Combined treatment with MAPK-pathway and histone-deacetylase inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF-MEK-ERK inhibition, which may be overcome by combining signalling- and chromatin-directed therapeutics.

Related: Melanoma Signal Transduction


Berthon A, Drelon C, Ragazzon B, et al.
WNT/β-catenin signalling is activated in aldosterone-producing adenomas and controls aldosterone production.
Hum Mol Genet. 2014; 23(4):889-905 [PubMed] Related Publications
Primary aldosteronism (PA) is the main cause of secondary hypertension, resulting from adrenal aldosterone-producing adenomas (APA) or bilateral hyperplasia. Here, we show that constitutive activation of WNT/β-catenin signalling is the most frequent molecular alteration found in 70% of APA. We provide evidence that decreased expression of the WNT inhibitor SFRP2 may be contributing to deregulated WNT signalling and APA development in patients. This is supported by the demonstration that mice with genetic ablation of Sfrp2 have increased aldosterone production and ectopic differentiation of zona glomerulosa cells. We further show that β-catenin plays an essential role in the control of basal and Angiotensin II-induced aldosterone secretion, by activating AT1R, CYP21 and CYP11B2 transcription. This relies on both LEF/TCF-dependent activation of AT1R and CYP21 regulatory regions and indirect activation of CYP21 and CYP11B2 promoters, through increased expression of the nuclear receptors NURR1 and NUR77. Altogether, these data show that aberrant WNT/β-catenin activation is associated with APA development and suggest that WNT pathway may be a good therapeutic target in PA.

Related: Adrenocortical Cancer Adrenocortical Carcinoma - Molecular Biology


Kolesar JM, Traynor AM, Holen KD, et al.
Vorinostat in combination with bortezomib in patients with advanced malignancies directly alters transcription of target genes.
Cancer Chemother Pharmacol. 2013; 72(3):661-7 [PubMed] Article available free on PMC after 18/02/2015 Related Publications
INTRODUCTION: Vorinostat is a small molecule inhibitor of class I and II histone deacetylase enzymes which alters the expression of target genes including the cell cycle gene p21, leading to cell cycle arrest and apoptosis.
METHODS: Patients enrolled in a phase I trial were treated with vorinostat alone on day 1 and vorinostat and bortezomib in combination on day 9. Paired biopsies were obtained in eleven subjects. Blood samples were obtained on days 1 and 9 of cycle 1 prior to dosing and 2 and 6 h post-dosing in all 60 subjects. Gene expression of p21, HSP70, AKT, Nur77, ERB1, and ERB2 was evaluated in peripheral blood mononuclear cells and tissue samples. Chromatin immunoprecipitation of p21, HSP70, and Nur77 was also performed in biopsy samples.
RESULTS: In peripheral blood mononuclear cells, Nur77 was significantly and consistently decreased 2 h after vorinostat administration on both days 1 and 9, median ratio of gene expression relative to baseline of 0.69 with interquartile range 0.49-1.04 (p < 0.001); 0.28 (0.15-0.7) (p < 0.001), respectively, with more pronounced decrease on day 9, when patients received both vorinostat and bortezomib. p21, a downstream target of Nur77, was significantly decreased on day 9, 2 and 6 h after administration of vorinostat and bortezomib, 0.67 (0.41-1.03) (p < 0.01); 0.44 (0.25-1.3) (p < 0.01), respectively. The ChIP assay demonstrated a protein-DNA interaction, in this case interaction of Nur77, HSP70 and p21 with acetylated histone H3, at baseline and at day 9 after treatment with vorinostat in tissue biopsies in most patients.
CONCLUSION: Vorinostat inhibits Nur77 expression, which in turn may decrease p21 and AKT expression in PBMCs. The influence of vorinostat on target gene expression in tumor tissue was variable; however, most patients demonstrated interaction of acetylated H3 with Nur77, HSP70, and p21 which provides evidence of interaction with the transcriptionally active acetylated H3.

Related: CDKN1A Cancer Prevention and Risk Reduction AKT1 Bortezomib


Yu L, Su YS, Zhao J, et al.
Repression of NR4A1 by a chromatin modifier promotes docetaxel resistance in PC-3 human prostate cancer cells.
FEBS Lett. 2013; 587(16):2542-51 [PubMed] Related Publications
Epigenetic silencing mechanisms play an important role in chemoresistance of human cancer. Here we report the upregulated expression of metastasis-associated protein 1 (MTA1), a component of the nucleosome remodeling deacetylation (NuRD) complex, in chemoresistant prostate cancer (PCa). MTA1 knockdown in PC-3 cells inhibited cell proliferation and enhanced docetaxel (DTX)-induced cell death. Conversely, overexpression of MTA1 promotes DTX chemoresistance in PC-3 cells. MTA1 acted as a potent corepressor of the nuclear receptor NR4A1 transcription by interacting with histone deacetylase 2 (HDAC2). These findings suggest that MTA1 may serve as a novel DTX-resistance promoter in PC-3 cells.

Related: Apoptosis Prostate Cancer Docetaxel


Wilson AJ, Liu AY, Roland J, et al.
TR3 modulates platinum resistance in ovarian cancer.
Cancer Res. 2013; 73(15):4758-69 [PubMed] Article available free on PMC after 18/02/2015 Related Publications
In metastatic ovarian cancer, resistance to platinum chemotherapy is common. Although the orphan nuclear receptor TR3 (nur77/NR4A1) is implicated in mediating chemotherapy-induced apoptosis in cancer cells, its role in ovarian cancer has not been determined. In an ovarian cancer tissue microarray, TR3 protein expression was elevated in stage I tumors, but downregulated in a significant subset of metastatic tumors. Moreover, TR3 expression was significantly lower in platinum-resistant tumors in patients with metastatic disease, and low TR3 staining was associated with poorer overall and progression-free survival. We have identified a direct role for TR3 in cisplatin-induced apoptosis in ovarian cancer cells. Nucleus-to-cytoplasm translocation of TR3 was observed in cisplatin-sensitive (OVCAR8, OVCAR3, and A2780PAR) but not cisplatin-resistant (NCI/ADR-RES and A2780CP20) ovarian cancer cells. Immunofluorescent analyses showed clear overlap between TR3 and mitochondrial Hsp60 in cisplatin-treated cells, which was associated with cytochrome c release. Ovarian cancer cells with stable shRNA- or transient siRNA-mediated TR3 downregulation displayed substantial reduction in cisplatin effects on apoptotic markers and cell growth in vitro and in vivo. Mechanistic studies showed that the cisplatin-induced cytoplasmic TR3 translocation required for apoptosis induction was regulated by JNK activation and inhibition of Akt. Finally, cisplatin resistance was partially overcome by ectopic TR3 overexpression and by treatment with the JNK activator anisomycin and Akt pathway inhibitor, wortmannin. Our results suggest that disruption of TR3 activity, via downregulation or nuclear sequestration, likely contributes to platinum resistance in ovarian cancer. Moreover, we have described a treatment strategy aimed at overcoming platinum resistance by targeting TR3.

Related: Ovarian Cancer Signal Transduction


Hu YL, Zhong D, Pang F, et al.
HNF1b is involved in prostate cancer risk via modulating androgenic hormone effects and coordination with other genes.
Genet Mol Res. 2013; 12(2):1327-35 [PubMed] Related Publications
Prostate cancer is one of the most commonly diagnosed male malignancies. Genome wide association studies have revealed HNF1b to be a major risk gene for prostate cancer susceptibility. We examined the mechanisms of involvement of HNF1b in prostate cancer development. We integrated data from Gene Expression Omnibus prostate cancer genes from the Dragon Database of Genes Implicated in Prostate Cancer, and used meta-analysis data to generate a panel of HNF1b-associated prostate cancer risk genes. An RT-PCR was used to assess expression levels in DU145, PC3, LNCaP, and RWEP-1 cells. Twelve genes (BAG1, DDR1, ERBB4, ESR1, HSPD1, IGFBP2, IGFBP5, NR4A1, PAWR, PIK3CG, RAP2A, and TPD52) were found to be associated with both HNF1b and prostate cancer risk. Six of them (BAG1, ERBB4, ESR1, HSPD1, NR4A1, and PIK3CG) were mapped to the KEGG pathway, and submitted to further gene expression assessment. HNF1b, NR4A1, and HSPD1 were found to be highly expressed in the LNCaP androgenic hormone-dependent cell line. Compared to expression levels in wild-type prostate cancer cells, NR4A1, HSPD1, ERBB4, and ESR1 expression levels were also found to be significantly increased in the HNF1b-transfected cells. We conclude that the mechanism of action of HNF1b in prostate cancer involves modulation of the association between androgenic hormone and prostate cancer cells. Gene-gene interaction and coordination should be taken into account to determine relationships between specific loci and diseases.

Related: Prostate Cancer Signal Transduction HNF1B


Yin H, Lo JH, Kim JY, et al.
Expression profiling of nuclear receptors identifies key roles of NR4A subfamily in uterine fibroids.
Mol Endocrinol. 2013; 27(5):726-40 [PubMed] Article available free on PMC after 18/02/2015 Related Publications
Uterine fibroids (UFs), also known as uterine leiomyomas, are benign, fibrotic smooth muscle tumors. Although the GnRH analog leuprolide acetate that suppresses gonadal steroid hormones is used as a treatment, it has significant side effects, thereby limiting its use. Availability of more effective therapy is limited because of a lack of understanding of molecular underpinnings of the disease. Although ovarian steroid hormones estrogen and progesterone and their receptors are clearly involved, the role of other nuclear receptors (NRs) in UFs is not well defined. We used quantitative real-time PCR to systematically profile the expression of 48 NRs and identified several NRs that were aberrantly expressed in UFs. Among others, expression of NR4A subfamily members including NGFIB (NR4A1), NURR1 (NR4A2), and NOR1 (NR4A3) were dramatically suppressed in leiomyoma compared with the matched myometrium. Restoration of expression of each of these NR4A members in the primary leiomyoma smooth muscle cells decreased cell proliferation. Importantly, NR4As regulate expressions of the profibrotic factors including TGFβ3 and SMAD3, and several collagens that are key components of the extracellular matrix. Finally, we identify NR4A members as targets of leuprolide acetate treatment. Together, our results implicate several NRs including the NR4A subfamily in leiomyoma etiology and identify NR4As as potential therapeutic targets for treating fibrotic diseases.


Vacca M, Murzilli S, Salvatore L, et al.
Neuron-derived orphan receptor 1 promotes proliferation of quiescent hepatocytes.
Gastroenterology. 2013; 144(7):1518-1529.e3 [PubMed] Related Publications
BACKGROUND & AIMS: Studies of the transcriptional networks that regulate nuclear receptor-mediated proliferation of quiescent hepatocytes could lead to new information about liver growth and hepatoprotective strategies.
METHODS: We used quantitative real-time PCR to analyze expression of neuron-derived orphan receptor 1 (Nor-1) and its target genes during liver regeneration after hepatectomy in mice, and in hepatocellular carcinoma (HCC) samples from patients. We used adenoviral vectors to express Nor-1 in normal liver (Ad/CMV/V5-Nor-1), or reduce its level with small hairpin RNAs (Ad/BLOCK-iT/Nor-1(small hairpin RNA)) after partial hepatectomy.
RESULTS: Levels of Nor-1 messenger RNA and protein, and transcription of Nor-1 target genes (Ccnd1 and Vcam-1), increased during the late priming and proliferative phases of liver regeneration after partial hepatectomy. Levels of NOR-1 messenger RNA and transcription of its target gene CCND1 and of the NOR-1 subfamily member NUR-77 also increased in human HCC samples compared with paired HCC-free tissue. Ad-Nor-1(small hairpin RNA) reduced the hepatocyte proliferation after hepatectomy. Overexpression of Nor-1 in normal livers of mice induced proliferation of quiescent hepatocytes independently of interleukin-6 and tumor necrosis factor-α signaling. In gene expression profile analysis, Nor-1 altered expression of genes involved in the cell cycle, proliferation, and tumorigenesis.
CONCLUSIONS: In mice, the orphan nuclear receptor Nor-1 activates proliferation of quiescent hepatocytes and is required for hepatocyte proliferation after partial hepatectomy. Nor-1 and its gene targets are also up-regulated in human HCC samples. Nor-1 activates a transcriptional program that induces hepatocyte proliferation independently of inflammatory signaling pathways.

Related: Liver Cancer


Watanuki Y, Takayasu S, Kageyama K, et al.
Involvement of Nurr-1/Nur77 in corticotropin-releasing factor/urocortin1-induced tyrosinase-related protein 1 gene transcription in human melanoma HMV-II cells.
Mol Cell Endocrinol. 2013; 370(1-2):42-51 [PubMed] Related Publications
Recent molecular and biochemical analyses have revealed the presence of corticotropin-releasing factor (CRF) and urocortin (Ucn), together with their corresponding receptors in mammalian skin. The melanosomal enzyme tyrosinase-related protein 1 (TRP1) is involved in modulation of pigment production in response to stressors. Although CRF and Ucn are thought to have potent effects on the skin system, their possible roles and regulation have yet to be fully determined. This study aimed to explore the effects of CRF and Ucn on TRP1 gene expression using human melanoma HMV-II cells. The mRNA of CRF, Ucn1, Ucn2, and CRF receptor type 1 (CRF1 receptor) was detected in HMV-II cells. CRF and Ucn1 stimulated TRP1 gene transcription via the CRF1 receptor, and increased both Nurr-1 and Nur77 mRNA expression levels. Both CRF- and Ucn1-induced Nurr-1/Nur77 acted via a NGFI-B response element on the TRP1 promoter. The combination of Nurr-1/Nur77 and microphthalmia-associated transcription factor, a melanocyte-specific transcription factor gene induced by α-melanocyte-stimulating hormone, had additive effects on activation of TRP1 gene transcription. The findings suggest that in human melanoma HMV-II cells both CRF and Ucn1 regulate TRP1 gene expression via Nurr-1/Nur77 production, independent of pro-opiomelanocortin or α-melanocyte-stimulating hormone stimulation.

Related: Melanoma


Vasilatos SN, Katz TA, Oesterreich S, et al.
Crosstalk between lysine-specific demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells.
Carcinogenesis. 2013; 34(6):1196-207 [PubMed] Article available free on PMC after 18/02/2015 Related Publications
Our previous studies demonstrated that lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) closely interact in controlling growth of breast cancer cells. However, the underlying mechanisms are largely unknown. In this study, we showed that knockdown of LSD1 expression (LSD1-KD) by RNAi decreased mRNA levels of HDAC isozymes in triple-negative breast cancer (TNBC) cells. Small interfering RNA (siRNA)-mediated depletion of HDAC5 expression induced the most significant accumulation of H3K4me2, a specific substrate of LSD1. Combined treatment with LSD1 inhibitor, pargyline, and HDAC inhibitor, SAHA (Vorinostat), led to superior growth inhibition and apoptotic death in TNBC cells, but exhibited additive or antagonistic effect on growth inhibition in non-TNBC counterparts or non-tumorigenic breast cells. Additionally, LSD1-KD enhanced SAHA-induced reexpression of a subset of aberrantly silenced genes, such as NR4A1, PCDH1, RGS16, BIK, and E-cadherin whose reexpression may be tumor suppressive. Genome-wide microarray study in MDA-MB-231 cells identified a group of tumor suppressor genes whose expression was induced by SAHA and significantly enhanced by LSD1-KD. We also showed that concurrent depletion of RGS16 by siRNA reduced overall cytotoxicity of SAHA and blocked the reexpression of E-cadherin, CDKN1C and ING1 in LSD1-deficient MDA-MB-231 cells. Furthermore, cotreatment with RGS16 siRNA reversed the downregulation of nuclear factor-kappaB expression induced by combined inhibition of LSD1 and HDACs, suggesting a crucial role of RGS16 in controlling key pathways of cell death in response to combination therapy. Taken together, these results provide novel mechanistic insight into the breast cancer subtype-dependent role of LSD1 in mediating HDAC activity and therapeutic efficacy of HDAC inhibitor.

Related: Apoptosis Breast Cancer BIK


Muscat GE, Eriksson NA, Byth K, et al.
Research resource: nuclear receptors as transcriptome: discriminant and prognostic value in breast cancer.
Mol Endocrinol. 2013; 27(2):350-65 [PubMed] Related Publications
To identify biologically relevant groupings or clusters of nuclear receptors (NR) that are associated with breast neoplasia, with potentially diagnostic, discriminant or prognostic value, we quantitated mRNA expression levels of all 48 members of the human NR superfamily by TaqMan low-density array analysis in 116 curated breast tissue samples, including pre- and postmenopausal normal breast and both ERα(+) and ERα(-) tumor tissue. In addition, we have determined NR levels in independent cohorts of tamoxifen-treated ERα(+) and ERα(-) tissue samples. There were differences in relative NR mRNA expression between neoplastic and normal breast, and between ER(+) and ER(-) tumors. First, there is overexpression of the NUR77 subgroup and EAR2 in neoplastic breast. Second, we identify a signature of five NR (ERα, EAR2, NUR77, TRα, and RARγ) that classifies breast samples with more than 97% cross-validated accuracy into normal or cancer classes. Third, we find a novel negative association between five NR (TRβ, NUR77, RORγ, COUP-TFII, and LRH1) and histological grade. Finally, four NR (COUP-TFII, TRβ, PPARγ, and MR) are significant predictors of metastasis-free survival in tamoxifen-treated breast cancers, independent of ER expression. The present study highlights the discriminant and prognostic value of NR in breast cancer; identifies novel, clinically relevant, NR signatures; and highlights NR signaling pathways with potential roles in breast cancer pathophysiology and as new therapeutic targets.

Related: Breast Cancer THRB PPARG gene


Hubmann R, Hilgarth M, Schnabl S, et al.
Gliotoxin is a potent NOTCH2 transactivation inhibitor and efficiently induces apoptosis in chronic lymphocytic leukaemia (CLL) cells.
Br J Haematol. 2013; 160(5):618-29 [PubMed] Related Publications
Chronic lymphocytic leukaemia (CLL) cells express constitutively activated NOTCH2 in a protein kinase C (PKC)- dependent manner. The transcriptional activity of NOTCH2 correlates not only with the expression of its target gene FCER2 (CD23) but is also functionally linked with CLL cell viability. In the majority of CLL cases, DNA-bound NOTCH2 complexes are less sensitive to the γ-secretase inhibitor (GSI) DAPT. Therefore, we searched for compounds that interfere with NOTCH2 signalling at the transcription factor level. Using electrophoretic mobility shift assays (EMSA), we identified the Aspergillum-derived secondary metabolite gliotoxin as a potent NOTCH2 transactivation inhibitor. Gliotoxin completely blocked the formation of DNA-bound NOTCH2 complexes in CLL cells independent of their sensitivity to DAPT. The inhibition of NOTCH2 signalling by gliotoxin was associated with down regulation of CD23 (FCER) expression and induction of apoptosis. Short time exposure of CLL cells indicated that the early apoptotic effect of gliotoxin is independent of proteasome regulated nuclear factor κB activity, and is associated with up regulation of NOTCH3 and NR4A1 expression. Gliotoxin could overcome the supportive effect of primary bone marrow stromal cells in an ex vivo CLL microenvironment model. In conclusion, we identified gliotoxin as a potent NOTCH2 inhibitor with a promising therapeutic potential in CLL.

Related: Apoptosis Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology NOTCH2 gene NOTCH3


Zhou L, Ruvolo VR, McQueen T, et al.
HDAC inhibition by SNDX-275 (Entinostat) restores expression of silenced leukemia-associated transcription factors Nur77 and Nor1 and of key pro-apoptotic proteins in AML.
Leukemia. 2013; 27(6):1358-68 [PubMed] Article available free on PMC after 18/02/2015 Related Publications
Nur77 and Nor1 are highly conserved orphan nuclear receptors. We have recently reported that nur77(-/-)nor1(-/-) mice rapidly develop acute myeloid leukemia (AML) and that Nur77 and Nor1 transcripts were universally downregulated in human AML blasts. These findings indicate that Nur77 and Nor1 function as leukemia suppressors. We further demonstrated silencing of Nur77 and Nor1 in leukemia stem cells (LSCs). We here report that inhibition of histone deacetylase (HDAC) using the specific class I HDAC inhibitor SNDX-275 restored the expression of Nur77/Nor1 and induced expression of activator protein 1 transcription factors c-Jun and JunB, and of death receptor TRAIL, in AML cells and in CD34(+)/38(-) AML LSCs. Importantly, SNDX-275 induced extensive apoptosis in AML cells, which could be suppressed by silencing nur77 and nor1. In addition, pro-apoptotic proteins Bim and Noxa were transcriptionally upregulated by SNDX-275 in AML cells and in LSCs. Our present work is the first report of a novel mechanism of HDAC inhibitor-induced apoptosis in AML that involves restoration of the silenced nuclear receptors Nur77 and Nor1, activation of activator protein 1 transcription factors, a death receptor and pro-apoptotic proteins.

Related: Apoptosis Acute Myeloid Leukemia (AML)


Clocchiatti A, Di Giorgio E, Ingrao S, et al.
Class IIa HDACs repressive activities on MEF2-depedent transcription are associated with poor prognosis of ER⁺ breast tumors.
FASEB J. 2013; 27(3):942-54 [PubMed] Related Publications
MEF2s transcription factors and class IIa HDACs compose a fundamental axis for several differentiation pathways. Functional relationships between this axis and cancer are largely unexplored. We have found that class IIa HDACs are heterogeneously expressed and display redundant activities in breast cancer cells. Applying gene set enrichment analysis to compare the expression profile of a list of putative MEF2 target genes, we have discovered a correlation between the down-regulation of the MEF2 signature and the aggressiveness of ER(+) breast tumors. Kaplan-Meier analysis in ER(+) breast tumors evidenced an association between increased class IIa HDACs expression and reduced survival. The important role of the MEF2-HDAC axis in ER(+) breast cancer was confirmed in cultured cells. MCF7 ER(+) cells were susceptible to silencing of class IIa HDACs in terms of both MEF2-dependent transcription and apoptosis. Conversely, in ER(-) MDA-MB-231 cells, the repressive influence of class IIa HDACs was dispensable. Similarly, a class IIa HDAC-specific inhibitor preferentially promoted the up-regulation of several MEF2 target genes and apoptosis in ER(+) cell lines. The prosurvival function of class IIa HDACs could be explained by the repression of NR4A1/Nur77, a proapoptotic MEF2 target. In summary, our studies underscore a contribution of class IIa HDACs to aggressiveness of ER(+) tumors.-Clocchiatti, A., Di Giorgio, E., Ingrao, S., Meyer-Almes, F.-J., Tripodo, C., Brancolini, C. Class IIa HDACs repressive activities on MEF2-depedent transcription are associated with poor prognosis of ER(+) breast tumors.

Related: Apoptosis Breast Cancer


Zhan YY, He JP, Chen HZ, et al.
Orphan receptor TR3 is essential for the maintenance of stem-like properties in gastric cancer cells.
Cancer Lett. 2013; 329(1):37-44 [PubMed] Related Publications
The orphan receptor TR3 is an important regulator of cell proliferation and apoptosis. However, whether TR3 is involved in regulating the stem-like properties of cancer cells remains unknown. The present study shows that TR3 expression is increased in gastric tumorsphere cells and is positively correlated with cancer stem cell (CSC) characteristics. Knocking down TR3 leads to the suppression of its stem-like properties in both gastric cancer cells and tumorsphere cells. This process involves the decreased expression of the stemness-related genes Oct-4 and Nanog and the invasion-related gene MMP-9. We further identify Nanog as a new target for the transcription factor TR3. Together, these data demonstrate for the first time that TR3 is essential for the maintenance of stem-like properties in human gastric cancer cells and implicate TR3 as a new therapeutic target for gastric cancer.

Related: MMP9: matrix metallopeptidase 9 Stomach Cancer Gastric Cancer


Liao S, Desouki MM, Gaile DP, et al.
Differential copy number aberrations in novel candidate genes associated with progression from in situ to invasive ductal carcinoma of the breast.
Genes Chromosomes Cancer. 2012; 51(12):1067-78 [PubMed] Article available free on PMC after 18/02/2015 Related Publications
Only a minority of intraductal carcinomas of the breast give rise to stromally invasive disease. We microdissected 206 paraffin blocks representing 116 different cases of low-grade ductal carcinoma in situ (DCIS). Fifty-five were pure DCIS (PD) cases without progression to invasive carcinoma. Sixty-one cases had a small invasive component. DNA was extracted from microdissected sections and hybridized to high-density bacterial artificial chromosome arrays. Array comparative genomic hybridization analysis of 118 hybridized DNA samples yielded data on 69 samples that were suitable for further statistical analysis. This cohort included 20 pure DCIS cases, 25 mixed DCIS (MD), and 24 mixed invasive carcinoma samples. PD cases had a higher frequency of DNA copy number changes than MD cases, and the latter had similar DNA profiles compared to paired invasive carcinomas. Copy number changes on 13 chromosomal arms occurred at different rates in PD versus MD lesions. Eight of 19 candidate genes residing at those loci were confirmed to have differential copy number changes by quantitative PCR. NCOR2/SMRT and NR4A1 (both on 12q), DYNLRB2 (16q), CELSR1, UPK3A, and ST13 (all on 22q) were more frequently amplified in PD. Moreover, NCOR2, NR4A1, and DYNLRB2 showed more frequent copy number losses in MD. GRAP2 (22q) was more often amplified in MD, whereas TAF1C (16q) was more commonly deleted in PD. A multigene model comprising these candidate genes discriminated between PD and MD lesions with high accuracy. These findings suggest that the propensity to invade the stroma may be encoded in the genome of intraductal carcinomas.

Related: Breast Cancer CGH


Spitz MR, Gorlov IP, Amos CI, et al.
Variants in inflammation genes are implicated in risk of lung cancer in never smokers exposed to second-hand smoke.
Cancer Discov. 2011; 1(5):420-9 [PubMed] Article available free on PMC after 18/02/2015 Related Publications
Lung cancer in lifetime never smokers is distinct from that in smokers, but the role of separate or overlapping carcinogenic pathways has not been explored. We therefore evaluated a comprehensive panel of 11,737 single-nucleotide polymorphisms (SNP) in inflammatory-pathway genes in a discovery phase (451 lung cancer cases, 508 controls from Texas). SNPs that were significant were evaluated in a second external population (303 cases, 311 controls from the Mayo Clinic). An intronic SNP in the ACVR1B gene, rs12809597, was replicated with significance and restricted to those reporting adult exposure to environmental tobacco smoke. Another promising candidate was an SNP in NR4A1, although the replication OR did not achieve statistical significance. ACVR1B belongs to the TGFR-β superfamily, contributing to resolution of inflammation and initiation of airway remodeling. An inflammatory microenvironment (second-hand smoking, asthma, or hay fever) is necessary for risk from these gene variants to be expressed. These findings require further replication, followed by targeted resequencing, and functional validation.

Related: Non-Small Cell Lung Cancer Lung Cancer


Deutsch AJ, Angerer H, Fuchs TE, Neumeister P
The nuclear orphan receptors NR4A as therapeutic target in cancer therapy.
Anticancer Agents Med Chem. 2012; 12(9):1001-14 [PubMed] Related Publications
NR4A1 (Nur77), NR4A2 (Nurr1) and NR4A3 (Nor-1) are three members of the orphan nuclear receptor (NR) family referred to as NR4A family. This subgroup activates gene expression in a constitutive ligand-independent manner. These nuclear receptors are classified as early response genes that are induced by a diverse range of signals. These orphan NRs have been implicated in cell cycle regulation, apoptosis, inflammation, metabolism and more recently in carcinogenesis. The ultimate growth of a tumor depends not only on the rate of tumor cell proliferation, but also the rate of apoptosis and NR4A1 controls both, survival and death of cancer cells. It has been demonstrated that NR4A1 activities are regulated through its subcellular localisation. In the nucleus, NR4A1 can function in a context dependent manner either as an oncogenic survival factor, promoting cancer cell growth or as the opposite through the activation of apoptosis. Additionally, in an atypical fashion, it is a potent killer when migrating to the mitochondria, where it binds to Bcl-2 and converts its survival phenotype, triggering cytochrome c release and apoptosis. The most convincing evidence that nuclear orphan receptors function as critical tumor suppressors is the observation that the NR4A1 and NR4A3 double knock out mouse develops rapidly acute myeloid leukemia. Down regulation of NR4A1 and NR4A3 was a common feature in leukemic blasts from human AML patients. In particular, the recent identification of pro-apoptotic agents inducing NR4A expression or acting as agonists suggests that these members could serve as potential targets for cancer therapy.

Related: Apoptosis Cancer Prevention and Risk Reduction


Mohan HM, Aherne CM, Rogers AC, et al.
Molecular pathways: the role of NR4A orphan nuclear receptors in cancer.
Clin Cancer Res. 2012; 18(12):3223-8 [PubMed] Related Publications
Nuclear receptors are of integral importance in carcinogenesis. Manipulation of classic ligand-activated nuclear receptors, such as estrogen receptor blockade in breast cancer, is an important established cancer therapy. Orphan nuclear receptors, such as nuclear family 4 subgroup A (NR4A) receptors, have no known natural ligand(s). These elusive receptors are increasingly recognized as molecular switches in cell survival and a molecular link between inflammation and cancer. NR4A receptors act as transcription factors, altering expression of downstream genes in apoptosis (Fas-ligand, TRAIL), proliferation, DNA repair, metabolism, cell migration, inflammation (interleukin-8), and angiogenesis (VEGF). NR4A receptors are modulated by multiple cell-signaling pathways, including protein kinase A/CREB, NF-κB, phosphoinositide 3-kinase/AKT, c-jun-NH(2)-kinase, Wnt, and mitogen-activated protein kinase pathways. NR4A receptor effects are context and tissue specific, influenced by their levels of expression, posttranslational modification, and interaction with other transcription factors (RXR, PPAR-Υ). The subcellular location of NR4A "nuclear receptors" is also important functionally; novel roles have been described in the cytoplasm where NR4A proteins act both indirectly and directly on the mitochondria to promote apoptosis via Bcl-2. NR4A receptors are implicated in a wide variety of malignancies, including breast, lung, colon, bladder, and prostate cancer; glioblastoma multiforme; sarcoma; and acute and/or chronic myeloid leukemia. NR4A receptors modulate response to conventional chemotherapy and represent an exciting frontier for chemotherapeutic intervention, as novel agents targeting NR4A receptors have now been developed. This review provides a concise clinical overview of current knowledge of NR4A signaling in cancer and the potential for therapeutic manipulation.

Related: Apoptosis Cancer Prevention and Risk Reduction Angiogenesis and Cancer Signal Transduction


To SK, Zeng JZ, Wong AS
Nur77: a potential therapeutic target in cancer.
Expert Opin Ther Targets. 2012; 16(6):573-85 [PubMed] Related Publications
INTRODUCTION: The orphan nuclear receptor Nur77 (also known as NR4A1, NGFIB, TR3, TIS1, NAK-1, or N10) is a unique transcription factor encoded by an immediate early gene. Nur77 signaling is deregulated in many cancers and constitutes an important molecule for drug targeting.
AREAS COVERED: Nur77 as a versatile transcription factor that displays distinct dual roles in cell proliferation and apoptosis. In addition, several recent insights into Nur77's non-genomic signaling through its physical interactions with various signaling proteins and its phosphorylation-dependent regulation will be highlighted. The possible mechanisms by which Nur77 supports carcinogenesis and specific examples in different human cancers will be summarized. Different approaches to target Nur77 using mimetics, natural products, and synthetic compounds are also described.
EXPERT OPINION: These latest findings shed light on the novel roles of Nur77 as an exploitable target for new cancer therapeutics. Further work which focuses on a more complete understanding of the Nur77 interactome as well as how the different networks of Nur77 functional interactions are orchestrated in a stimulus or context-specific way will aid the development of more selective, non-toxic approaches for targeting Nur77 in future.

Related: Cancer Prevention and Risk Reduction


Halldórsdóttir AM, Kanduri M, Marincevic M, et al.
Mantle cell lymphoma displays a homogenous methylation profile: a comparative analysis with chronic lymphocytic leukemia.
Am J Hematol. 2012; 87(4):361-7 [PubMed] Related Publications
Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are mature CD5(+) B-cell malignancies with different biological/clinical characteristics. We recently reported an association between different prognostic subgroups of CLL (i.e., IGHV mutated and unmutated) and genomic methylation pattern. However, the relationship between DNA methylation and prognostic markers, such as the proliferation gene expression signature, has not been investigated in MCL. We applied high-resolution methylation microarrays (27,578 CpG sites) to assess the global DNA methylation profiles in 20 MCL (10 each with high/low proliferation signature) and 30 CLL (15 poor-prognostic IGHV unmutated subset #1 and 15 good-prognostic IGHV mutated subset #4) samples. Notably, MCL and each CLL subset displayed distinct genomic methylation profiles. After unsupervised hierarchical clustering, 17/20 MCL cases formed a cluster separate from CLL, while CLL subsets #1 and #4 formed subclusters. Surprisingly, few differentially methylated genes (n = 6) were identified between high vs. low proliferation MCL. In contrast, distinct methylation profiles were demonstrated for MCL and CLL. Importantly, certain functional classes of genes were preferentially methylated in either disease. For instance, developmental genes, in particular homeobox transcription factor genes (e.g., HLXB9, HOXA13), were more highly methylated in MCL, whereas apoptosis-related genes were enriched among targets methylated in CLL (e.g., CYFIP2, NR4A1). Results were validated using pyrosequencing, RQ-PCR and reexpression of specific genes. In summary, the methylation profile of MCL was homogeneous and no correlation with the proliferation signature was observed. Compared to CLL, however, marked differences were discovered such as the preferential methylation of homeobox genes in MCL.

Related: Azacitidine Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology Mantle Cell Lymphoma


Yao LM, He JP, Chen HZ, et al.
Orphan receptor TR3 participates in cisplatin-induced apoptosis via Chk2 phosphorylation to repress intestinal tumorigenesis.
Carcinogenesis. 2012; 33(2):301-11 [PubMed] Related Publications
Cisplatin is a widely used antitumor agent that induces aggressive cancer cell death via triggering cellular proteins involved in apoptosis. Here, we demonstrate that cisplatin effectively induces orphan nuclear receptor TR3 phosphorylation by activating Chk2 kinase activity and promoting cross talk between these two proteins, thereby contributing to the repression of intestinal tumorigenesis via apoptosis. Mechanistic analysis has demonstrated that Chk2-induced phosphorylation enables TR3 to bind to its response elements on the promoters of the BRE and RNF-7 genes, leading to the negative regulation of these two anti-apoptotic genes. Furthermore, the induction of apoptosis by cisplatin is mediated by TR3, and knockdown of TR3 reduces cisplatin-induced apoptosis in colon cancer cells by 27%. The role of TR3 in cisplatin chemotherapy is further clarified in mouse models. In Apc(min/+) mice, cisplatin inhibits intestinal tumorigenesis by 70% in a TR3 phosphorylation-dependent manner; however, the loss of TR3 function in Apc(min/+)/TR3(-/-) mice leads to the failure of cisplatin-induced repression of tumorigenesis. Consistently, xenografts derived from TR3 knockdown colon cancer cells are insensitive to cisplatin treatment, whereas a significant curative effect (50% inhibition) is observed in xenografts with functional TR3. Taken together, our study reveals a novel cross talk between Chk2 and TR3 and sheds light on the mechanism of cisplatin-induced apoptosis through TR3. Therefore, TR3 may be a new target of cisplatin for colon cancer therapy.

Related: Apoptosis CHEK2 Cisplatin


Gogna R, Madan E, Kuppusamy P, Pati U
Reactive oxygen species-mediated p53 core-domain modifications determine apoptotic or necrotic death in cancer cells.
Antioxid Redox Signal. 2012; 16(5):400-12 [PubMed] Related Publications
AIMS: p53 is known to induce apoptotic and necrotic cell death in response to stress, although the mechanism of these pathways is unknown. The aim of this study was to determine the molecular mechanism that determines p53's decision to select the apoptotic or necrotic mode of cell death.
RESULTS: Gold nanoparticles (Au-NPs) induced both apoptosis and necrosis in cancer cells in a p53-dependent manner. In cells undergoing apoptosis and necrosis, differential patterns of reactive oxygen species (ROS) generation were observed that leads to the activation of two different sets of p53-interacting kinases and acetylases. The differential activation of cellular kinases and acetylases caused dissimilar patterns of p53 phosphorylation and acetylation. In apoptotic cells, p53 was post-translationally modified in the core-domain, whereas in necrotic cells, it was modified at both N- and C-terminii, thus displaying differential DNA-binding activity. Au-NP10 and Au-NP80 activated fifty apoptotic and fifty nine necrotic p53-downstream genes, respectively. Both Au-NP10 and Au-NP80 showed HCT (p53+/+) tumor regression in mice xenografts.
INNOVATION: This study established for the first time that, in cancer cells, Au-NP-mediated apoptosis and necrosis are controlled by differential activation of p53 and its downstream genes. Further, both Au-NP10 and Au-NP80 were shown to regress HCT (p53+/+) tumors via apoptotic and necrotic pathways, respectively.
CONCLUSION: Au-NP-mediated p53 activation at both transcription and proteome level, through ROS-mediated p53 post-translational modification pattern, is responsible for tumor regression, which may further find wider application of nanoparticles in cancer therapy.

Related: Apoptosis Cancer Prevention and Risk Reduction TP53


Lee SO, Andey T, Jin UH, et al.
The nuclear receptor TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53.
Oncogene. 2012; 31(27):3265-76 [PubMed] Article available free on PMC after 18/02/2015 Related Publications
The orphan nuclear receptor TR3 (NR41A and Nur77) is overexpressed in most lung cancer patients and is a negative prognostic factor for patient survival. The function of TR3 was investigated in non-small-cell lung cancer A549 and H460 cells, and knockdown of TR3 by RNA interference (siTR3) inhibited cancer cell growth and induced apoptosis. The prosurvival activity of TR3 was due, in part, to formation of a p300/TR3/ specificity protein 1 complex bound to GC-rich promoter regions of survivin and other Sp-regulated genes (mechanism 1). However, in p53 wild-type A549 and H460 cells, siTR3 inhibited the mTORC1 pathway, and this was due to activation of p53 and induction of the p53-responsive gene sestrin 2, which subsequently activated the mTORC1 inhibitor AMP-activated protein kinase α (AMPKα) (mechanism 2). This demonstrates that the pro-oncogenic activity of TR3 in lung cancer cells was due to inhibition of p53 and activation of mTORC1. 1,1-Bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) is a recently discovered inhibitor of TR3, which mimics the effects of siTR3. DIM-C-pPhOH inhibited growth and induced apoptosis in lung cancer cells and lung tumors in murine orthotopic and metastatic models, and this was accompanied by decreased expression of survivin and inhibition of mTORC1 signaling, demonstrating that inactivators of TR3 represent a novel class of mTORC1 inhibitors.

Related: Non-Small Cell Lung Cancer Lung Cancer Signal Transduction TP53


Holla VR, Wu H, Shi Q, et al.
Nuclear orphan receptor NR4A2 modulates fatty acid oxidation pathways in colorectal cancer.
J Biol Chem. 2011; 286(34):30003-9 [PubMed] Article available free on PMC after 18/02/2015 Related Publications
Although cancer cells have traditionally been thought to rely on the glycolytic pathway to generate ATP, recent studies suggest that cancer cells can shift to the fatty acid oxidation pathway as an alternative energy source. All of the factors that induce and regulate this adaptive shift in metabolism are not known. Cyclooxygenase-2-derived prostaglandin E(2) (PGE(2)) is produced at high levels in colon cancer, and multiple lines of evidence from human-, animal-, and cell line-based studies indicate that PGE(2) plays a pro-oncogenic role in colorectal cancer progression. We have shown previously that exposure of colon cancer cells to PGE(2) promotes cell survival, in part by inducing the expression of the nuclear orphan receptor NR4A2. Here, we report that PGE(2)-induced NR4A2 increased fatty acid oxidation by inducing the expression of multiple proteins in the fatty acid oxidation pathway. NR4A2 was found to bind directly to Nur77-binding response elements located within the regulatory region of these genes. Nur77-binding response element binding also resulted in the recruitment of transcriptional coactivators and induction of gene expression. Collectively, our findings suggest that NR4A2 plays a key role as a transcriptional integration point between the eicosanoid and fatty acid metabolic pathways. Thus, PGE(2) is a potential regulator of the adaptive shift to energy utilization via fatty acid oxidation that has been observed in several types of cancer.

Related: Colorectal (Bowel) Cancer


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Cite this page: Cotterill SJ. NR4A1, Cancer Genetics Web: http://www.cancerindex.org/geneweb/NR4A1.htm Accessed: date

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