BRD3

Gene Summary

Gene:BRD3; bromodomain containing 3
Aliases: ORFX, RING3L
Location:9q34.2
Summary:This gene was identified based on its homology to the gene encoding the RING3 protein, a serine/threonine kinase. The gene localizes to 9q34, a region which contains several major histocompatibility complex (MHC) genes. The function of the encoded protein is not known. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:bromodomain-containing protein 3
Source:NCBIAccessed: 15 March, 2017

Ontology:

What does this gene/protein do?
Show (9)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 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.

  • VHL
  • Young Adult
  • Antineoplastic Agents
  • Up-Regulation
  • Xenograft Models
  • Azepines
  • Transcriptome
  • Cell Differentiation
  • Benzodiazepines
  • Translocation
  • Epigenetics
  • Transcription
  • HeLa Cells
  • Chromatin
  • Gene Rearrangement
  • Nuclear Proteins
  • Signal Transduction
  • Protein Binding
  • Acute Myeloid Leukaemia
  • siRNA
  • Cell Cycle
  • Heterocyclic Compounds, 4 or More Rings
  • Triazoles
  • Models, Molecular
  • Cancer Gene Expression Regulation
  • Transcription Factors
  • Apoptosis
  • Breast Cancer
  • BRD3
  • Cell Proliferation
  • Membrane Proteins
  • Thymus Neoplasms
  • Chromosome 9
  • Oncogene Fusion Proteins
  • Epigenomics
  • Lung Cancer
  • Carcinoma
  • Oncogene Proteins
  • Gene Expression Profiling
  • Childhood Cancer
  • RNA-Binding Proteins
  • Protein-Serine-Threonine Kinases
Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

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

Latest Publications: BRD3 (cancer-related)

Andrieu G, Belkina AC, Denis GV
Clinical trials for BET inhibitors run ahead of the science.
Drug Discov Today Technol. 2016; 19:45-50 [PubMed] Article available free on PMC after 21/07/2017 Related Publications
Several cancer clinical trials for small molecule inhibitors of BET bromodomain proteins have been initiated. There is enthusiasm for the anti-proliferative effect of inhibiting BRD4, one of the targets of these inhibitors, which is thought to cooperate with MYC, a long-desired target for cancer therapeutics. However, no current inhibitor is selective for BRD4 among the three somatic BET proteins, which include BRD2 and BRD3; their respective functions are partially overlapping and none are functionally redundant with BRD4. Each BET protein controls distinct transcriptional pathways that are important for functions beyond cancer cell proliferation, including insulin production, cytokine gene transcription, T cell differentiation, adipogenesis and most seriously, active repression of dangerous latent viruses like HIV. BET inhibitors have been shown to reactivate HIV in human cells. Failure to appreciate that at concentrations used, no available BET inhibitor is member-selective, or to develop a sound biological basis to understand the diverse functions of BET proteins before undertaking for these clinical trials is reckless and likely to lead to adverse events. More mechanistic information from new basic science studies should enable proper focus on the most relevant cancers and define the expected side effect profiles.

Hensel T, Giorgi C, Schmidt O, et al.
Targeting the EWS-ETS transcriptional program by BET bromodomain inhibition in Ewing sarcoma.
Oncotarget. 2016; 7(2):1451-63 [PubMed] Article available free on PMC after 21/07/2017 Related Publications
Ewing sarcomas (ES) are highly malignant bone or soft tissue tumors. Genetically, ES are defined by balanced chromosomal EWS/ETS translocations, which give rise to chimeric proteins (EWS-ETS) that generate an oncogenic transcriptional program associated with altered epigenetic marks throughout the genome. By use of an inhibitor (JQ1) blocking BET bromodomain binding proteins (BRDs) we strikingly observed a strong down-regulation of the predominant EWS-ETS protein EWS-FLI1 in a dose dependent manner. This was further enhanced by co-treatment with an inhibitor of the PI3K pathway. Microarray analysis further revealed JQ1 treatment to block a typical ES associated expression program. The effect on this expression program was mimicked by RNA interference with BRD3 or BRD4 expression, indicating that the EWS-FLI1 mediated expression profile is at least in part mediated via such epigenetic readers. Consequently, contact dependent and independent proliferation of different ES lines was strongly inhibited. Mechanistically, treatment of ES resulted in a partial arrest of the cell cycle as well as induction of apoptosis. Tumor development was suppressed dose dependently in a xeno-transplant model in immune deficient mice, overall indicating that ES may be susceptible to treatment with epigenetic inhibitors blocking BET bromodomain activity and the associated pathognomonic EWS-ETS transcriptional program.

Borbely G, Haldosen LA, Dahlman-Wright K, Zhao C
Induction of USP17 by combining BET and HDAC inhibitors in breast cancer cells.
Oncotarget. 2015; 6(32):33623-35 [PubMed] Article available free on PMC after 21/07/2017 Related Publications
Members of the bromodomain and extra-C terminal (BET) domain protein family and the histone deacetylase (HDAC) enzyme family regulate the expression of important oncogenes and tumor suppressor genes. Here we show that the BET inhibitor JQ1 inhibits proliferation and induces apoptosis of both triple negative and estrogen receptor positive breast cancer cells. Consistent with the critical role of histone acetylation in the regulation of gene expression, treatment with JQ1 or the HDAC inhibitor mocetinostat was associated with global changes in gene expression resulting in suppression of genes involved in cell-cycle regulation. Combining JQ1 with mocetinostat, further decreased cell viability. This synergistic effect was associated with increased suppression of genes essential for cell-cycle progression. Furthermore, we detected dramatic increase in the expression of several members of the ubiquitin-specific protease 17 (USP17) family of deubiquitinating enzymes in response to the combination treatment. Increased expression of USP17 enzymes were able to attenuate the Ras/MAPK pathway causing decrease in cell viability, while, siRNA mediated depletion of USP17 significantly decreased cytotoxicity after the combination treatment. In conclusion, our study demonstrates that co-treatment with BET inhibitors and HDAC inhibitors reduces breast cancer cell viability through induction of USP17.

Ran X, Zhao Y, Liu L, et al.
Structure-Based Design of γ-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors.
J Med Chem. 2015; 58(12):4927-39 [PubMed] Related Publications
Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, and BRD4 proteins have therapeutic potential for the treatment of human cancers and other diseases and conditions. In this paper, we report the design, synthesis, and evaluation of γ-carboline-containing compounds as a new class of small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain proteins (BRD2, BRD3, and BRD4) with Ki values of 3.2-24.7 nM and demonstrates high selectivity over other non-BET bromodomain-containing proteins. Compound 18 potently and selectively inhibits cell growth in human acute leukemia cell lines harboring the rearranged mixed lineage leukemia 1 gene. We have determined a cocrystal structure of 18 in complex with BRD4 BD2 at 1.4 Å resolution, which provides a solid structural basis for the compound's high binding affinity and for its further structure-based optimization. Compound 18 represents a promising lead compound for the development of a new class of therapeutics for the treatment of human cancer and other conditions.

Zengerle M, Chan KH, Ciulli A
Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4.
ACS Chem Biol. 2015; 10(8):1770-7 [PubMed] Article available free on PMC after 21/07/2017 Related Publications
The Bromo- and Extra-Terminal (BET) proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation, epigenetics, and cancer and are the targets of pan-BET selective bromodomain inhibitor JQ1. However, the lack of intra-BET selectivity limits the scope of current inhibitors as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We designed Proteolysis Targeted Chimeras (PROTACs) that tether JQ1 to a ligand for the E3 ubiquitin ligase VHL, aimed at triggering the intracellular destruction of BET proteins. Compound MZ1 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 over BRD2 and BRD3. The activity of MZ1 is dependent on binding to VHL but is achieved at a sufficiently low concentration not to induce stabilization of HIF-1α. Gene expression profiles of selected cancer-related genes responsive to JQ1 reveal distinct and more limited transcriptional responses induced by MZ1, consistent with selective suppression of BRD4. Our discovery opens up new opportunities to elucidate the cellular phenotypes and therapeutic implications associated with selective targeting of BRD4.

Coudé MM, Braun T, Berrou J, et al.
BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells.
Oncotarget. 2015; 6(19):17698-712 [PubMed] Article available free on PMC after 21/07/2017 Related Publications
The bromodomain (BRD) and extraterminal (BET) proteins including BRD2, BRD3 and BRD4 have been identified as key targets for leukemia maintenance. A novel oral inhibitor of BRD2/3/4, the thienotriazolodiazepine compound OTX015, suitable for human use, is available. Here we report its biological effects in AML and ALL cell lines and leukemic samples. Exposure to OTX015 lead to cell growth inhibition, cell cycle arrest and apoptosis at submicromolar concentrations in acute leukemia cell lines and patient-derived leukemic cells, as described with the canonical JQ1 BET inhibitor. Treatment with JQ1 and OTX15 induces similar gene expression profiles in sensitive cell lines, including a c-MYC decrease and an HEXIM1 increase. OTX015 exposure also induced a strong decrease of BRD2, BRD4 and c-MYC and increase of HEXIM1 proteins, while BRD3 expression was unchanged. c-MYC, BRD2, BRD3, BRD4 and HEXIM1 mRNA levels did not correlate however with viability following exposure to OTX015. Sequential combinations of OTX015 with other epigenetic modifying drugs, panobinostat and azacitidine have a synergic effect on growth of the KASUMI cell line. Our results indicate that OTX015 and JQ1 have similar biological effects in leukemic cells, supporting OTX015 evaluation in a Phase Ib trial in relapsed/refractory leukemia patients.

Dragoescu E, French C, Cassano A, et al.
NUT midline carcinoma presenting with bilateral ovarian metastases: a case report.
Int J Gynecol Pathol. 2015; 34(2):136-42 [PubMed] Related Publications
Nuclear protein of the testis (NUT) midline carcinoma (NMC) is an uncommon, relatively recently characterized carcinoma, which is defined by NUT gene rearrangements. We are reporting a case of NMC in a 38-year-old female who presented with pleural effusion and bilateral ovarian masses. We also discuss some of the difficulties encountered by the practicing pathologist in reaching the diagnosis and the role of ancillary studies. Immunohistochemical staining using a commercially available monoclonal antibody showing nuclear expression of the NUT protein is diagnostic of NMC. Dual-color split-apart fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR) can be used to characterize the fusion gene, whether BRD4-NUT or BRD3-NUT, or NUT-variant.

Suzuki S, Kurabe N, Ohnishi I, et al.
NSD3-NUT-expressing midline carcinoma of the lung: first characterization of primary cancer tissue.
Pathol Res Pract. 2015; 211(5):404-8 [PubMed] Related Publications
BACKGROUND: Nuclear protein in testis (NUT) midline carcinoma (NMC) is a rare, aggressive malignancy. Only two pediatric and three adult cases of pulmonary NMCs have been documented. In more than two-thirds of NMC cases, a gene fusion between NUT and BRD4 or BRD3 has been documented; other fusions are rare.
CASE PRESENTATION: A 36-year-old woman was admitted because of a rapidly progressing tumor of the lung with metastases to the breast and bone. A biopsy from the lung tumor revealed an undifferentiated neoplasm exhibiting round to oval nuclei with vesicular chromatin, prominent nucleoli, and scant cytoplasm. Immunohistochemical staining demonstrated focal EMA, cytokeratin AE1/AE3, cytokeratin CAM 5.2, p63, CD138, and vimentin positivity. Finally, the nuclear staining pattern for NUT confirmed a histopathological diagnosis of NMC. A 5'- rapid amplification of the cDNA end (RACE) procedure successfully identified the partner of the NUT translocation as NSD3, a recently discovered partner. Fluorescence in situ hybridization confirmed the NSD3-NUT gene rearrangement, whereas a BRD3/4-NUT fusion gene was not detected.
CONCLUSION: We herein describe the first case of an NSD3-NUT-expressing NMC of the lung. The further accumulation of variant NMCs should provide clues to the establishment of new individualized therapy for NMCs.

Gallagher SJ, Mijatov B, Gunatilake D, et al.
The epigenetic regulator I-BET151 induces BIM-dependent apoptosis and cell cycle arrest of human melanoma cells.
J Invest Dermatol. 2014; 134(11):2795-805 [PubMed] Related Publications
Epigenetic changes are widespread in melanoma and contribute to the pathogenic biology of this disease. In the present study, we show that I-BET151, which belongs to a new class of drugs that target the BET family of epigenetic "reader" proteins, inhibits melanoma growth in vivo and induced variable degrees of apoptosis in a panel of melanoma cells. Apoptosis was caspase dependent and associated with G1 cell cycle arrest. All melanoma cells tested had increased levels of the BH3 proapoptotic protein BIM, which appeared to be regulated by the BRD2 BET protein and to some extent by BRD3. In contrast, knockdown experiments indicated that inhibition of BRD4 was associated with decreased levels of BIM. Apoptosis was dependent on BIM in some but not all cell lines, indicating that other factors were determinants of apoptosis, such as downregulation of antiapoptotic proteins revealed in gene expression arrays. G1 cell cycle arrest appeared to be mediated by p21 and resulted from inhibition of the BRD4 protein. The activity of BET protein inhibitors appears independent of the BRAF and NRAS mutational status of melanoma, and further studies to assess their therapeutic role in melanoma are warranted.

Shi J, Vakoc CR
The mechanisms behind the therapeutic activity of BET bromodomain inhibition.
Mol Cell. 2014; 54(5):728-36 [PubMed] Article available free on PMC after 21/07/2017 Related Publications
The bromodomain and extraterminal (BET) protein Brd4 recruits transcriptional regulatory complexes to acetylated chromatin. While Brd4 is considered to be a general transcriptional regulator, pharmacological inhibition of BET proteins shows therapeutic activity in a variety of different pathologies, particularly in models of cancer and inflammation. Such effects have been attributed to a specific set of downstream target genes whose expression is disproportionately sensitive to pharmacological targeting of BET proteins. Emerging evidence links the transcriptional consequences of BET inhibition to the association of Brd4 with enhancer elements, which tend to be involved in lineage-specific gene regulation. Furthermore, Brd4 engages in direct regulatory interactions with several DNA-binding transcription factors to influence their disease-relevant functions. Here we review the current understanding of molecular mechanisms that underlie the promising therapeutic effects of BET bromodomain inhibition.

Feng Q, Zhang Z, Shea MJ, et al.
An epigenomic approach to therapy for tamoxifen-resistant breast cancer.
Cell Res. 2014; 24(7):809-19 [PubMed] Article available free on PMC after 21/07/2017 Related Publications
Tamoxifen has been a frontline treatment for estrogen receptor alpha (ERα)-positive breast tumors in premenopausal women. However, resistance to tamoxifen occurs in many patients. ER still plays a critical role in the growth of breast cancer cells with acquired tamoxifen resistance, suggesting that ERα remains a valid target for treatment of tamoxifen-resistant (Tam-R) breast cancer. In an effort to identify novel regulators of ERα signaling, through a small-scale siRNA screen against histone methyl modifiers, we found WHSC1, a histone H3K36 methyltransferase, as a positive regulator of ERα signaling in breast cancer cells. We demonstrated that WHSC1 is recruited to the ERα gene by the BET protein BRD3/4, and facilitates ERα gene expression. The small-molecule BET protein inhibitor JQ1 potently suppressed the classic ERα signaling pathway and the growth of Tam-R breast cancer cells in culture. Using a Tam-R breast cancer xenograft mouse model, we demonstrated in vivo anti-breast cancer activity by JQ1 and a strong long-lasting effect of combination therapy with JQ1 and the ER degrader fulvestrant. Taken together, we provide evidence that the epigenomic proteins BRD3/4 and WHSC1 are essential regulators of estrogen receptor signaling and are novel therapeutic targets for treatment of Tam-R breast cancer.

Pastori C, Daniel M, Penas C, et al.
BET bromodomain proteins are required for glioblastoma cell proliferation.
Epigenetics. 2014; 9(4):611-20 [PubMed] Article available free on PMC after 21/07/2017 Related Publications
Epigenetic proteins have recently emerged as novel anticancer targets. Among these, bromodomain and extra terminal domain (BET) proteins recognize lysine-acetylated histones, thereby regulating gene expression. Newly described small molecules that inhibit BET proteins BRD2, BRD3, and BRD4 reduce proliferation of NUT (nuclear protein in testis)-midline carcinoma, multiple myeloma, and leukemia cells in vitro and in vivo. These findings prompted us to determine whether BET proteins may be therapeutic targets in the most common primary adult brain tumor, glioblastoma (GBM). We performed NanoString analysis of GBM tumor samples and controls to identify novel therapeutic targets. Several cell proliferation assays of GBM cell lines and stem cells were used to analyze the efficacy of the drug I-BET151 relative to temozolomide (TMZ) or cell cycle inhibitors. Lastly, we performed xenograft experiments to determine the efficacy of I-BET151 in vivo. We demonstrate that BRD2 and BRD4 RNA are significantly overexpressed in GBM, suggesting that BET protein inhibition may be an effective means of reducing GBM cell proliferation. Disruption of BRD4 expression in glioblastoma cells reduced cell cycle progression. Similarly, treatment with the BET protein inhibitor I-BET151 reduced GBM cell proliferation in vitro and in vivo. I-BET151 treatment enriched cells at the G1/S cell cycle transition. Importantly, I-BET151 is as potent at inhibiting GBM cell proliferation as TMZ, the current chemotherapy treatment administered to GBM patients. Since I-BET151 inhibits GBM cell proliferation by arresting cell cycle progression, we propose that BET protein inhibition may be a viable therapeutic option for GBM patients suffering from TMZ resistant tumors.

Wyce A, Ganji G, Smitheman KN, et al.
BET inhibition silences expression of MYCN and BCL2 and induces cytotoxicity in neuroblastoma tumor models.
PLoS One. 2013; 8(8):e72967 [PubMed] Article available free on PMC after 21/07/2017 Related Publications
BET family proteins are epigenetic regulators known to control expression of genes involved in cell growth and oncogenesis. Selective inhibitors of BET proteins exhibit potent anti-proliferative activity in a number of hematologic cancer models, in part through suppression of the MYC oncogene and downstream Myc-driven pathways. However, little is currently known about the activity of BET inhibitors in solid tumor models, and whether down-regulation of MYC family genes contributes to sensitivity. Here we provide evidence for potent BET inhibitor activity in neuroblastoma, a pediatric solid tumor associated with a high frequency of MYCN amplifications. We treated a panel of neuroblastoma cell lines with a novel small molecule inhibitor of BET proteins, GSK1324726A (I-BET726), and observed potent growth inhibition and cytotoxicity in most cell lines irrespective of MYCN copy number or expression level. Gene expression analyses in neuroblastoma cell lines suggest a role of BET inhibition in apoptosis, signaling, and N-Myc-driven pathways, including the direct suppression of BCL2 and MYCN. Reversal of MYCN or BCL2 suppression reduces the potency of I-BET726-induced cytotoxicity in a cell line-specific manner; however, neither factor fully accounts for I-BET726 sensitivity. Oral administration of I-BET726 to mouse xenograft models of human neuroblastoma results in tumor growth inhibition and down-regulation MYCN and BCL2 expression, suggesting a potential role for these genes in tumor growth. Taken together, our data highlight the potential of BET inhibitors as novel therapeutics for neuroblastoma, and suggest that sensitivity is driven by pleiotropic effects on cell growth and apoptotic pathways in a context-specific manner.

Picaud S, Da Costa D, Thanasopoulou A, et al.
PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains.
Cancer Res. 2013; 73(11):3336-46 [PubMed] Article available free on PMC after 21/07/2017 Related Publications
Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are transcriptional regulators required for efficient expression of several growth promoting and antiapoptotic genes as well as for cell-cycle progression. BET proteins are recruited on transcriptionally active chromatin via their two N-terminal bromodomains (BRD), a protein interaction module that specifically recognizes acetylated lysine residues in histones H3 and H4. Inhibition of the BET-histone interaction results in transcriptional downregulation of a number of oncogenes, providing a novel pharmacologic strategy for the treatment of cancer. Here, we present a potent and highly selective dihydroquinazoline-2-one inhibitor, PFI-1, which efficiently blocks the interaction of BET BRDs with acetylated histone tails. Cocrystal structures showed that PFI-1 acts as an acetyl-lysine (Kac) mimetic inhibitor efficiently occupying the Kac binding site in BRD4 and BRD2. PFI-1 has antiproliferative effects on leukemic cell lines and efficiently abrogates their clonogenic growth. Exposure of sensitive cell lines with PFI-1 results in G1 cell-cycle arrest, downregulation of MYC expression, as well as induction of apoptosis and induces differentiation of primary leukemic blasts. Intriguingly, cells exposed to PFI-1 showed significant downregulation of Aurora B kinase, thus attenuating phosphorylation of the Aurora substrate H3S10, providing an alternative strategy for the specific inhibition of this well-established oncology target.

French CA
The importance of diagnosing NUT midline carcinoma.
Head Neck Pathol. 2013; 7(1):11-6 [PubMed] Article available free on PMC after 21/07/2017 Related Publications
NUT midline carcinoma (NMC) is an aggressive subset of squamous cell carcinoma, genetically defined by rearrangement of the NUT gene. The rearrangements most often take the form of BRD4-NUT fusions, and in a minority of cases, BRD3-NUT or NUT-variant fusions. The simple karyotypes of NMCs, in contrast to the complex ones of typical squamous cell carcinoma, suggest an alternate, genetic shortcut to squamous cancer. Although originally thought to be a disease of the mediastinum, NMC frequently (35 %) arises in the head and neck. Diagnosis is made simply by demonstration of nuclear immunoreactivity to NUT protein, and ancillary studies to characterize the fusion oncogene, though not required for diagnosis, are recommended. The prognosis is dismal, with a 6.7 month median survival, and treatment with conventional chemotherapeutic regimens is ineffective. The oncogenic mechanism of the dual bromodomains and the p300-binding portion of BRD4-NUT is to sequester p300 to localized regions of chromatin, leading to global transcriptional repression and blockade of differentiation. Two therapies which target this mechanism have emerged, including bromodomain inhibitors (BETi) and histone deacetylase inhibitors (HDACi), both of which induce differentiation and growth arrest of NMC cells, both in vitro and in vivo. BETi is available to adults with NMC through a phase I clinical trial, and clinical response to HDACi has been demonstrated in pediatric patients. The emergence of these promising targeted therapies gives hope that NMC may one day be effectively treated and provides a strong rationale for diagnostic testing for NMC.

Petrini P, French CA, Rajan A, et al.
NUT rearrangement is uncommon in human thymic epithelial tumors.
J Thorac Oncol. 2012; 7(4):744-50 [PubMed] Article available free on PMC after 21/07/2017 Related Publications
INTRODUCTION: Thymic carcinomas represent the most aggressive histotype of thymic epithelial tumors (TETs). The 2004 World Health Organization classification has assigned a subgroup of thymic carcinomas as t(15;19) carcinomas based on the presence of t(15;19), a translocation found in poorly differentiated and highly aggressive NUT midline carcinomas. These tumors are characterized byrearrangement of the NUT (nuclear protein in testis) gene on chromosome 15q14, which in most cases fuses to the bromodomain containing 4 (BRD4) gene on chromosome 19 p13.1 through reciprocal t(15;19) translocation, resulting in constitutive BRD4-NUTfusion protein expression. To our knowledge, NUT translocation has been reported only in four thymic carcinomas. Due to the rarity of TETs, the prevalence of NUT rearrangement in TETs has however never been systematically explored.
METHODS: Formalin-fixed paraffin-embedded samples of histologically confirmed TETs were evaluated for NUT expression and rearrangement by immunohistochemistry and fluorescence in situ hybridization, respectively.
RESULTS: A series of 148 TETs (37 carcinomas and 111 thymomas) were examined for NUT expression and rearrangement. Only one thymic carcinoma (2.7% of thymic carcinomas or 0.68% of TETs) was found positive for NUT expression and rearrangement.
CONCLUSIONS: Rearrangement of NUT is infrequent in TETs. We propose that caution should be taken to distinguish t(15;19) thymic carcinoma from other mediastinal carcinomas, as NUT midline carcinomas are often associated with dreadful prognosis or overt lethality.

French CA
Pathogenesis of NUT midline carcinoma.
Annu Rev Pathol. 2012; 7:247-65 [PubMed] Related Publications
NUT midline carcinoma (NMC), an aggressive form of squamous cell carcinoma, is defined by the presence of acquired chromosomal rearrangements involving NUT, usually BRD4-NUT fusion genes and, less commonly, NUT-variant fusion genes involving BRD3 or still-uncharacterized genes. Improved diagnostic tests reveal that although rare, NMCs occur in people of any age and may be indistinguishable from more common squamous cell carcinomas of adulthood. NMCs have simple karyotypes whose hallmark is genomic instability, suggesting that NMC arises through a distinct pathogenic pathway representing a genetic shortcut to the phenotype of squamous cell carcinoma. Mechanistically, BRD-NUT fusion proteins appear to act by blocking differentiation, possibly by sequestering histone acetyltransferase activity. Accordingly, histone deacetylase inhibitors or BET inhibitors, the latter of which inhibit binding of BRD-NUT proteins to chromatin, induce terminal differentiation of NMC cells. These insights provide a rationale for targeted therapy of NMC, which is almost uniformly refractory to conventional chemotherapy and radiotherapy.

Dawson MA, Prinjha RK, Dittmann A, et al.
Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia.
Nature. 2011; 478(7370):529-33 [PubMed] Article available free on PMC after 21/07/2017 Related Publications
Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC and the polymerase-associated factor complex (PAFc), are associated with the BET family of acetyl-lysine recognizing, chromatin 'adaptor' proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. We show that a novel small molecule inhibitor of the BET family, GSK1210151A (I-BET151), has profound efficacy against human and murine MLL-fusion leukaemic cell lines, through the induction of early cell cycle arrest and apoptosis. I-BET151 treatment in two human leukaemia cell lines with different MLL fusions alters the expression of a common set of genes whose function may account for these phenotypic changes. The mode of action of I-BET151 is, at least in part, due to the inhibition of transcription at key genes (BCL2, C-MYC and CDK6) through the displacement of BRD3/4, PAFc and SEC components from chromatin. In vivo studies indicate that I-BET151 has significant therapeutic value, providing survival benefit in two distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukaemia. Finally, the efficacy of I-BET151 against human leukaemia stem cells is demonstrated, providing further evidence of its potent therapeutic potential. These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias.

French CA
NUT midline carcinoma.
Cancer Genet Cytogenet. 2010; 203(1):16-20 [PubMed] Article available free on PMC after 21/07/2017 Related Publications
NUT midline carcinoma (NMC) is a rare, aggressive human cancer, genetically defined by rearrangements of the gene NUT (HUGO symbol: C15orf55). In the majority (∼75%) of NMCs, most of the coding sequence of NUT on chromosome 15q14 is fused with BRD4 creating chimeric genes that encode BRD-NUT fusion proteins. In the remaining cases, NUT is fused to BRD3 or an unknown partner gene; these tumors are termed NUT-variant. Diagnosis of NMC is made by demonstration of expression of the NUT-fusion protein using a monoclonal antibody to NUT for immunohistochemistry, and confirmation of the fusion (BRD-NUT or NUT-variant) by fluorescent in situ hybridization or reverse transcriptase-polymerase chain reaction. BRD-NUT functions to block cellular differentiation and promote uncontrolled growth of carcinoma cells. Because the reagents and expertise required to diagnose NMC are not available in most laboratories, and because of incomplete awareness of this disease, NMC is frequently undiagnosed or misdiagnosed, and its actual prevalence is unknown. NUT midline carcinoma does not arise from any specific tissue type or organ. It presents as a poorly differentiated carcinoma originating from midline locations such as the head, neck or mediastinum. Although rare, NMCs occur throughout life, and advanced local disease is frequently accompanied by distant hematogenous metastases. There still is no effective treatment for NMC, there are no guidelines, and current approaches to treatment are based on discussions among a few oncologists who each have had a single experience treating this disease.

Zhang L, Deng T, Li X, et al.
microRNA-141 is involved in a nasopharyngeal carcinoma-related genes network.
Carcinogenesis. 2010; 31(4):559-66 [PubMed] Related Publications
microRNAs (miRNAs) are small non-coding RNAs and have been implicated in the pathology of various diseases, including cancer. Here we report that the miRNA profiles have been changed after knockdown of one of the most important oncogene c-MYC or re-expression of a candidate tumor suppressor gene SPLUNC1 in nasopharyngeal carcinoma (NPC) cells. Both c-MYC knockdown and SPLUNC1 re-expression can down-regulate microRNA-141 (miR-141). miR-141 is up-regulated in NPC specimens in comparison with normal nasopharyngeal epithelium. Inhibition of miR-141 could affect cell cycle, apoptosis, cell growth, migration and invasion in NPC cells. We found that BRD3, UBAP1 and PTEN are potential targets of miR-141, which had been confirmed following luciferase reporter assays and western blotting. BRD3 and UBAP1 are both involved in NPC carcinogenesis as confirmed through our previous studies and PTEN is a crucial tumor suppressor in many tumor types. BRD3 is involved in the regulation of the Rb/E2F pathway. Inhibition of miR-141 could affect some important molecules in the Rb/E2F, JNK2 and AKT pathways. It is well known that carcinogenesis of NPC is involved in the networks of genetic and epigenetic alteration events. We propose that miR-141- and tumor-related genes c-MYC, SPLUNC1, BRD3, UBAP1 and PTEN may constitute a gene-miRNA network to contribute to NPC development.

Shehata BM, Steelman CK, Abramowsky CR, et al.
NUT midline carcinoma in a newborn with multiorgan disseminated tumor and a 2-year-old with a pancreatic/hepatic primary.
Pediatr Dev Pathol. 2010 Nov-Dec; 13(6):481-5 [PubMed] Related Publications
NUT midline carcinoma (NMC) is a rare and aggressive malignant epithelial tumor defined by rearrangement of the NUT gene on chromosome 15. In two thirds of cases, NUT is involved in a balanced translocation with BDR4 on chromosome 19, while in the remaining cases, NUT is rearranged with variant fusion partners such as BRD3. These undifferentiated tumors primarily affect midline structures, usually in the upper aerodigestive tract and mediastinum. Most reported cases have followed a rapidly lethal clinical course. We report the clinical and pathological findings of NMC in the youngest patients identified so far. The 1st case involves a newborn who presented with a supraorbital mass and extensive multiorgan involvement, including the spine, lungs, liver, pancreas, adrenal glands, and subcutaneous tissue. The 2nd patient was a 2-year-old male with an abdominal mass involving the liver and pancreas with pulmonary metastasis. Histopathological analysis of both tumors showed undifferentiated malignant neoplasms, and immunohistochemistry showed positivity for epithelial markers. Both tumors demonstrated t(15;19), and immunohistochemistry with NUT monoclonal antibodies and fluorescent in situ hybridization confirmed NUT rearrangement. The patients died from disease at 1 and 2 months postpresentation. Thus far, 25 cases have been reported, including our 2 current cases. Presentation ages range from 0 to 78 years (mean, 23 years). Herein, we report the 2 youngest reported cases of NMC, including the 1st congenital case and the 1st case arising within the liver/pancreas. Increased awareness and further molecular studies are required for a better understanding of NMC pathobiology and improved therapeutic outcomes.

French CA
Demystified molecular pathology of NUT midline carcinomas.
J Clin Pathol. 2010; 63(6):492-6 [PubMed] Related Publications
NUT midline carcinoma (NMC) is a rare, highly lethal cancer that occurs in children and adults of all ages. NMCs uniformly present in the midline, most commonly in the head, neck or mediastinum, as poorly differentiated carcinomas with variable degrees of squamous differentiation. This tumour is defined by rearrangement of the nuclear protein in testis (NUT) gene on chromosome 15q14. In most cases, NUT is involved in a balanced translocation with the BRD4 gene on chromosome 19p13.1, an event that creates a BRD4-NUT fusion gene. Variant rearrangements, some involving the BRD3 gene, occur in the remaining cases. NMC is diagnosed by detection of NUT rearrangement by fluorescence in situ hybridisation or reverse transcriptase PCR. Due its rarity and lack of characteristic histological features, most cases of NMC currently go unrecognised.

French CA, Ramirez CL, Kolmakova J, et al.
BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells.
Oncogene. 2008; 27(15):2237-42 [PubMed] Related Publications
An unusual group of carcinomas, here termed nuclear protein in testis (NUT) midline carcinomas (NMC), are characterized by translocations that involve NUT, a novel gene on chromosome 15. In about 2/3rds of cases, NUT is fused to BRD4 on chromosome 19. Using a candidate gene approach, we identified two NMCs harboring novel rearrangements that result in the fusion of NUT to BRD3 on chromosome 9. The BRD3-NUT fusion gene encodes a protein composed of two tandem chromatin-binding bromodomains, an extra-terminal domain, a bipartite nuclear localization sequence, and almost the entirety of NUT that is highly homologous to BRD4-NUT. The function of NUT is unknown, but here we show that NUT contains nuclear localization and export sequences that promote nuclear-cytoplasmic shuttling via a leptomycin-sensitive pathway. In contrast, BRD3-NUT and BRD4-NUT are strictly nuclear, implying that the BRD moiety retains NUT in the nucleus via interactions with chromatin. Consistent with this idea, FRAP studies show that BRD4, BRD4-NUT and BRD3-NUT have significantly slower rates of lateral nuclear diffusion than that of NUT. To investigate the functional role of BRD-NUT fusion proteins in NMCs, we investigated the effects of siRNA-induced BRD3-NUT and BRD4-NUT withdrawal. Silencing of these proteins in NMC cell lines resulted in squamous differentiation and cell cycle arrest. Together, these data suggest that BRD-NUT fusion proteins contribute to carcinogenesis by associating with chromatin and interfering with epithelial differentiation.

Wu SY, Chiang CM
The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation.
J Biol Chem. 2007; 282(18):13141-5 [PubMed] Related Publications
Brd4 is a double bromodomain-containing protein that binds preferentially to acetylated chromatin. It belongs to the BET (bromodomains and extraterminal) family that includes mammalian Brd2, Brd3, Brd4, Brdt, Drosophila Fsh, yeast Bdf1, Bdf2, and corresponding homologues in other species. Brd4 is essential for cellular growth and has been implicated in cell cycle control, DNA replication, and gene rearrangement found in t(15;19)-associated carcinomas. Recently, Brd4 has been found in several transcription complexes, including the general cofactor Mediator and the P-TEFb elongation factor, and is capable of stimulating HIV-1 transcription in a Tat-independent manner. In addition, Brd4 is used as a cellular adaptor by some animal and human papillomaviruses (HPV) for anchoring viral genomes to mitotic chromosomes. This tethering, mediated by Brd4 interaction with virus-encoded E2 protein, facilitates viral genome segregation during mitosis. Interestingly, Brd4 is also identified in a transcriptional silencing complex assembled by HPV E2 and turns out to be the long sought cellular corepressor that inhibits the expression of HPV-encoded E6 and E7 oncoproteins that antagonize p53 and pRB tumor suppressor activity, respectively. The dual role of Brd4 in gene activation and repression illustrates how a dynamic chromatin-binding adaptor is able to recruit distinct transcriptional regulators to modulate promoter activity through cell cycle progression.

Ishii H, Mimori K, Mori M, Vecchione A
Differentially expressed genes in endothelial differentiation.
DNA Cell Biol. 2005; 24(7):432-7 [PubMed] Related Publications
By screening differentially expressed genes in mouse embryonic stem (ES) cells by subtractive hybridization, we identified three conserved but uncharacterized genes encoding bromodomain containing 3 (BRD3), protein lysine methyltransferase (PLM), and kelch domain containing 2 (KLHDC2), which were downregulated during endothelial differentiation. An RNA blot study showed that these genes were markedly expressed in undifferentiated ES cells, whereas the expression was reduced upon endothelial differentiation; a study of mouse endothelium showed a significant reduction in the expression of BRD3. A study of human BRD3, located on chromosome 9 at q34, a region susceptible to genomic rearrangement, showed an altered expression in 4 of 12 patients with bladder cancer, compared with adjacent noncancerous tissues. Taken together with the result of siRNA inhibition showing the positive regulation of cell proliferation by BRD3, it is suggested that this molecule plays a role in allowing cells to enter the proliferative phase of the angiogenic process.

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