NCOA1

Gene Summary

Gene:NCOA1; nuclear receptor coactivator 1
Aliases: SRC1, KAT13A, RIP160, F-SRC-1, bHLHe42, bHLHe74
Location:2p23.3
Summary:The protein encoded by this gene acts as a transcriptional coactivator for steroid and nuclear hormone receptors. It is a member of the p160/steroid receptor coactivator (SRC) family and like other family members has histone acetyltransferase activity and contains a nuclear localization signal, as well as bHLH and PAS domains. The product of this gene binds nuclear receptors directly and stimulates the transcriptional activities in a hormone-dependent fashion. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:nuclear receptor coactivator 1
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 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.

  • Transcription Factor AP-1
  • Vesicular Transport Proteins
  • Biomarkers, Tumor
  • Immunohistochemistry
  • Young Adult
  • Signal Transduction
  • Twist-Related Protein 1
  • Nuclear Proteins
  • Tumor Suppressor Proteins
  • Nuclear Receptor Coactivator 2
  • Ubiquitin-Protein Ligases
  • Promoter Regions
  • Histone Acetyltransferases
  • Prostate Cancer
  • Breast Cancer
  • Androgen Receptors
  • Nuclear Receptor Coactivator 3
  • Up-Regulation
  • Xenopus
  • Chromosome 2
  • Cell Proliferation
  • p300-CBP Transcription Factors
  • Vitamin D
  • Bladder Cancer
  • Cancer Gene Expression Regulation
  • VEGFA
  • Nuclear Receptor Coactivator 1
  • Messenger RNA
  • United Kingdom
  • Transcription Factors
  • Estrogen Receptors
  • p53 Protein
  • Taiwan
  • Trans-Activators
  • DNA-Binding Proteins
  • Molecular Sequence Data
  • Transcription
  • Repressor Proteins
  • Translocation
  • Transfection
  • Single Nucleotide Polymorphism
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: NCOA1 (cancer-related)

Andreasen S, Bishop JA, Hellquist H, et al.
Biphenotypic sinonasal sarcoma: demographics, clinicopathological characteristics, molecular features, and prognosis of a recently described entity.
Virchows Arch. 2018; 473(5):615-626 [PubMed] Related Publications
Biphenotypic sinonasal sarcoma (BSNS) is a recently recognized type of sarcoma arising exclusively in the sinonasal tract displaying unique clinical course, histopathology, and genetics. Due to its rarity, only case series and case reports are available. In order to provide an overview of the current understanding of this disease, we present a comprehensive review of the literature and present three previously unreported cases of BSNS. A total of 55 genetically characterized and 41 cases without molecular data were identified in the literature. Two-thirds of patients were female and the peak incidence was in the fifth decade. Fatal outcome was rare (two cases with intracranial extension) and local recurrence occurred in 31.6%, all occurring within 5 years after initial treatment. Histologically, BSNS is highly cellular in the majority of cases and composed of fascicles of spindle cells, with entrapped hyperplastic surface epithelium being a frequent finding. The immunohistochemical profile is characteristic due to the biphasic nature of this lesion, with shared features of both myogenic and neural origin. Rhabdomyoblastic differentiation is apparent in a subset of cases. The most common genetic event is the PAX3-MAML3 fusion (58.6%) but isolated PAX3 rearrangement (19.2%), absence of rearrangements (9.1%), PAX3-FOXO1 (8.1%), PAX3-NCOA1 (4%), and isolated MAML3 rearrangement (2%) have also been reported. In conclusion, the recognition of BSNS is crucial due to its relatively indolent clinical course. A selected immunohistochemical panel and/or molecular confirmation can be used to aid in appropriate diagnosis and consequently in prognostication and to avoid overtreatment with chemotherapy regimens used in its mimics.

Culig Z, Santer FR
Studies on Steroid Receptor Coactivators in Prostate Cancer.
Methods Mol Biol. 2018; 1786:259-262 [PubMed] Related Publications
High expression of several androgen receptor coactivators is frequently reported in prostate cancer. Coactivators such as p300/CBP are involved in modulation of androgen receptor activity by increasing the effects of androgenic hormones and enhancing agonistic activity of antiandrogens. Studies in the field of prostate cancer frequently examined the role of p300/CBP and SRC-1 (NCOA1). In addition to their effects on steroid receptor activity, coactivators may influence other cellular functions such as migration and invasion. Steroid receptor coactivators may target various downstream genes, thus modulating proliferative and migratory responses in specific prostate cancer models. This chapter will focus on methodologies used to analyze the role of steroid receptor coactivators in prostate cancer.

Gao B, Guo L, Luo D, et al.
Steroid receptor coactivator-1 interacts with NF-κB to increase VEGFC levels in human thyroid cancer.
Biosci Rep. 2018; 38(3) [PubMed] Free Access to Full Article Related Publications
Thyroid cancer is the most common endocrine cancer, and has a high incidence of lymphatic metastasis. Vascular endothelial growth factor C (VEGFC) is essential for development of lymphatic vessels and lymphatic metastases during carcinogenesis. Steroid receptor coactivator-1 (SRC-1) interacts with nuclear receptors and transcription factors to promote tumor proliferation and metastasis. However, the correlation between SRC-1 and VEGFC levels in the lymphatic metastases of thyroid cancer remains unclear. We analyzed 20-paired specimens of thyroid cancer tissue and normal thyroid tissue and found increased levels of SRC-1 and VEGFC proteins in 13/20 and 15/20 thyroid cancer specimens, respectively, when compared with those levels in specimens of normal thyroid tissue. A high level of SRC-1 expression was positively correlated with VEGFC and lymphatic endothelial cell marker LYVE-1 expression. Papillary thyroid carcinoma cell line TPC-1 displayed high levels of SRC-1 and VEGFC expression and was selected for stable knockdown of

Browne AL, Charmsaz S, Varešlija D, et al.
Network analysis of SRC-1 reveals a novel transcription factor hub which regulates endocrine resistant breast cancer.
Oncogene. 2018; 37(15):2008-2021 [PubMed] Free Access to Full Article Related Publications
Steroid receptor coactivator 1 (SRC-1) interacts with nuclear receptors and other transcription factors (TFs) to initiate transcriptional networks and regulate downstream genes which enable the cancer cell to evade therapy and metastasise. Here we took a top-down discovery approach to map out the SRC-1 transcriptional network in endocrine resistant breast cancer. First, rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) was employed to uncover new SRC-1 TF partners. Next, RNA sequencing (RNAseq) was undertaken to investigate SRC-1 TF target genes. Molecular and patient-derived xenograft studies confirmed STAT1 as a new SRC-1 TF partner, important in the regulation of a cadre of four SRC-1 transcription targets, NFIA, SMAD2, E2F7 and ASCL1. Extended network analysis identified a downstream 79 gene network, the clinical relevance of which was investigated in RNAseq studies from matched primary and local-recurrence tumours from endocrine resistant patients. We propose that SRC-1 can partner with STAT1 independently of the estrogen receptor to initiate a transcriptional cascade and control regulation of key endocrine resistant genes.

Azariadis K, Kiagiadaki F, Pelekanou V, et al.
Androgen Triggers the Pro-Migratory CXCL12/CXCR4 Axis in AR-Positive Breast Cancer Cell Lines: Underlying Mechanism and Possible Implications for the Use of Aromatase Inhibitors in Breast Cancer.
Cell Physiol Biochem. 2017; 44(1):66-84 [PubMed] Related Publications
BACKGROUND/AIMS: Reports regarding the role of androgen in breast cancer (BC) are conflicting. Some studies suggest that androgen could lead to undesirable responses in the presence of certain BC tumor characteristics. We have shown that androgen induces C-X-C motif chemokine 12 (CXCL12) in BC cell lines. Our aim was to identify the mechanisms regulating the phenotypic effects of androgen-induced CXCL12 on Androgen Receptor (AR) positive BC cell lines.
METHODS: We analyzed the expression of CXCL12 and its receptors with qPCR and ELISA and the role of Nuclear Receptor Coactivator 1 (NCOA1) in this effect. AR effects on the CXCL12 promoter was studied via Chromatin-immunoprecipitation. We also analyzed publically available data from The Cancer Genome Atlas to verify AR-CXCL12 interactions and to identify the effect or Aromatase Inhibitors (AI) therapy on CXCL12 expression and disease progression in AR positive cases.
RESULTS: CXCL12 induction occurs only in AR-positive BC cell lines, possibly via an Androgen Response Element, upstream of the CXCL12 promoter. The steroid receptor co-regulator NCOA1 is critical for this effect. Androgen only induced the motility of p53-mutant BC cells T47D cells via upregulation of CXCR4 expression while they had no effect on wild-type p53 MCF-7 cells. Loss of CXCR4 expression and depletion of CXCL12 abolished the effect of androgen in T47D cells while inhibition of p53 expression in MCF-7 cells made them responsive to androgen and increased their motility in the presence to androgen. Patients with estrogen receptor positive (ER+)/AR+ BC treated with AIs were at increased risk of disease progression compared to ER+/AR+ non-AI treated and ER+/AR- AI treated cases.
CONCLUSION: AIs may lead to unfavorable responses in some ER/AR positive BC cases, especially in patients with AR+, p53 mutant tumors.

Jeong H, Kim J, Kim Y
Identification of Linkages between EDCs in Personal Care Products and Breast Cancer through Data Integration Combined with Gene Network Analysis.
Int J Environ Res Public Health. 2017; 14(10) [PubMed] Free Access to Full Article Related Publications
Approximately 1000 chemicals have been reported to possibly have endocrine disrupting effects, some of which are used in consumer products, such as personal care products (PCPs) and cosmetics. We conducted data integration combined with gene network analysis to: (i) identify causal molecular mechanisms between endocrine disrupting chemicals (EDCs) used in PCPs and breast cancer; and (ii) screen candidate EDCs associated with breast cancer. Among EDCs used in PCPs, four EDCs having correlation with breast cancer were selected, and we curated 27 common interacting genes between those EDCs and breast cancer to perform the gene network analysis. Based on the gene network analysis, ESR1, TP53, NCOA1, AKT1, and BCL6 were found to be key genes to demonstrate the molecular mechanisms of EDCs in the development of breast cancer. Using GeneMANIA, we additionally predicted 20 genes which could interact with the 27 common genes. In total, 47 genes combining the common and predicted genes were functionally grouped with the gene ontology and KEGG pathway terms. With those genes, we finally screened candidate EDCs for their potential to increase breast cancer risk. This study highlights that our approach can provide insights to understand mechanisms of breast cancer and identify potential EDCs which are in association with breast cancer.

Magani F, Peacock SO, Rice MA, et al.
Targeting AR Variant-Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities.
Mol Cancer Res. 2017; 15(11):1469-1480 [PubMed] Free Access to Full Article Related Publications
Castration-resistant prostate cancer (CRPC) progresses rapidly and is incurable. Constitutively active androgen receptor splice variants (AR-Vs) represent a well-established mechanism of therapeutic resistance and disease progression. These variants lack the AR ligand-binding domain and, as such, are not inhibited by androgen deprivation therapy (ADT), which is the standard systemic approach for advanced prostate cancer. Signaling by AR-Vs, including the clinically relevant AR-V7, is augmented by Vav3, an established AR coactivator in CRPC. Using mutational and biochemical studies, we demonstrated that the Vav3 Diffuse B-cell lymphoma homology (DH) domain interacted with the N-terminal region of AR-V7 (and full length AR). Expression of the Vav3 DH domain disrupted Vav3 interaction with and enhancement of AR-V7 activity. The Vav3 DH domain also disrupted AR-V7 interaction with other AR coactivators: Src1 and Vav2, which are overexpressed in PC. This Vav3 domain was used in proof-of-concept studies to evaluate the effects of disrupting the interaction between AR-V7 and its coactivators on CRPC cells. This disruption decreased CRPC cell proliferation and anchorage-independent growth, caused increased apoptosis, decreased migration, and resulted in the acquisition of morphological changes associated with a less aggressive phenotype. While disrupting the interaction between FL-AR and its coactivators decreased N-C terminal interaction, disrupting the interaction of AR-V7 with its coactivators decreased AR-V7 nuclear levels.

Peng M, Zhao G, Yang F, et al.
NCOA1 is a novel susceptibility gene for multiple myeloma in the Chinese population: A case-control study.
PLoS One. 2017; 12(3):e0173298 [PubMed] Free Access to Full Article Related Publications
Multiple myeloma (MM) is an incurable malignancy of mature B-lymphoid cells, and its pathogenesis is only partially understood. Previous studies have demonstrated that a number of Non-Hodgkin Lymphoma (NHL) associated genes also show susceptibility to MM, suggesting malignancies originating from B cells may share similar genetic susceptibility. Several recent large-scale genome-wide association studies (GWAS) have identified HLA-I, HLA-II, CXCR5, ETS1, LPP and NCOA1 genes as genetic risk factors associated with NHL, and this study aimed to investigate whether these genes polymorphisms confer susceptibility with MM in the Chinese Han population. In 827 MM cases and 709 healthy controls of Chinese Han, seven single nucleotide polymorphisms (SNPs) in the HLA-I region (rs6457327), the HLA-II region (rs2647012 and rs7755224), the CXCR5 gene (rs4938573), the ETS1 gene (rs4937362), the LPP gene (rs6444305), and the NCOA1 region (rs79480871) were genotyped using the Sequenom platform. Our study indicated that genotype and allele frequencies of rs79480871 showed strong associations with MM patients (pa = 3.5×10-4 and pa = 1.5×10-4), and the rs6457327 genotype was more readily associated with MM patients than with controls (pa = 4.9×10-3). This study was the first to reveal the correlation between NCOA1 gene polymorphisms and MM patients, indicating that NCOA1 might be a novel susceptibility gene for MM patients in the Chinese Han population.

Ma YS, Wu TM, Lv ZW, et al.
High expression of miR-105-1 positively correlates with clinical prognosis of hepatocellular carcinoma by targeting oncogene NCOA1.
Oncotarget. 2017; 8(7):11896-11905 [PubMed] Free Access to Full Article Related Publications
Increasing evidence supports that microRNA (miRNA) plays a significant functional role in cancer progression by directly regulating respective targets. In this study, the expression levels of miR-105-1 and its target gene were analyzed using genes microarray and hierarchical clustering analysis followed by validation with quantitative RT-PCR in hepatocellular carcinoma (HCC) and normal liver tissues. We examined the expression of nuclear receptor coactivator 1 (NCOA1), the potential target gene of miR-105-1, following the transfection of miR-105-1 mimics or inhibitors. Our results showed that miR-105-1 was downregulated in HCC tissues when compared with normal liver tissues and patients with lower miR-105-1 expression had shorter overall survival (OS) and progression free survival (PFS). Moreover, NCOA1 was confirmed to be a direct target of miR-105-1. Furthermore, concomitant high expression of NCOA1 and low expression of miR-105-1 correlated with a shorter median OS and PFS in HCC patients. In conclusion, our results provide the first evidence that NCOA1 is a direct target of miR-105-1 suggesting that NCOA1 and miR-105-1 may have potential prognostic value and may be useful as tumor biomarkers for the diagnosis of HCC patients.

Arnold MA, Barr FG
Molecular diagnostics in the management of rhabdomyosarcoma.
Expert Rev Mol Diagn. 2017; 17(2):189-194 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: A classification of rhabdomyosarcoma (RMS) with prognostic relevance has primarily relied on clinical features and histologic classification as either embryonal or alveolar RMS. The PAX3-FOXO1 and PAX7-FOXO1 gene fusions occur in 80% of cases with the alveolar subtype and are more predictive of outcome than histologic classification. Identifying additional molecular hallmarks that further subclassify RMS is an active area of research. Areas Covered: The authors review the current state of the PAX3-FOXO1 and PAX7-FOXO1 fusions as prognostic biomarkers. Emerging biomarkers, including mRNA expression profiling, MYOD1 mutations, RAS pathway mutations and gene fusions involving NCOA2 or VGLL2 are also reviewed. Expert commentary: Strategies for modifying RMS risk stratification based on molecular biomarkers are emerging with the potential to transform the clinical management of RMS, ultimately improving patient outcomes by tailoring therapy to predicted patient risk and identifying targets for novel therapies.

Meerson A, Yehuda H
Leptin and insulin up-regulate miR-4443 to suppress NCOA1 and TRAF4, and decrease the invasiveness of human colon cancer cells.
BMC Cancer. 2016; 16(1):882 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Obesity is a risk factor for colorectal cancer (CRC). Normal and tumor cells respond to metabolic hormones, such as leptin and insulin. Thus, obesity-associated resistance to these hormones likely leads to changes in gene expression and behavior of tumor cells. However, the mechanisms affected by leptin and insulin signaling in CRC cells remain mostly unknown.
METHODS: We hypothesized that microRNAs (miRNAs) are involved in the regulation of tumorigenesis-related gene expression in CRC cells by leptin and insulin. To test this hypothesis, miRNA levels in the CRC-derived cell lines HCT-116, HT-29 and DLD-1 were profiled, following leptin and insulin treatment. Candidate miRNAs were validated by RT-qPCR. Predicted miRNA targets with known roles in cancer, were validated by immunoblots and reporter assays in HCT-116 cells. Transfection of HCT-116 cells with candidate miRNA mimic was used to test in vitro effects on proliferation and invasion.
RESULTS: Of ~800 miRNAs profiled, miR-4443 was consistently up-regulated by leptin and insulin in HCT-116 and HT-29, but not in DLD-1, which lacked normal leptin receptor expression. Dose response experiments showed that leptin at 100 ng/ml consistently up-regulated miR-4443 in HCT-116 cells, concomitantly with a significant decrease in cell invasion ability. Transfection with miR-4443 mimic decreased invasion and proliferation of HCT-116 cells. Moreover, leptin and miR-4443 transfection significantly down-regulated endogenous NCOA1 and TRAF4, both predicted targets of miR-4443 with known roles in cancer metastasis. miR-4443 was found to directly regulate TRAF4 and NCOA1, as validated by a reporter assay. The up-regulation of miR-4443 by leptin or insulin was attenuated by the inhibition of MEK1/2.
CONCLUSIONS: Our findings suggest that miR-4443 acts in a tumor-suppressive manner by down-regulating TRAF4 and NCOA1 downstream of MEK-C/EBP-mediated leptin and insulin signaling, and that insulin and/or leptin resistance (e.g. in obesity) may suppress this pathway and increase the risk of metastatic CRC.

Panagopoulos I, Gorunova L, Viset T, Heim S
Gene fusions AHRR-NCOA2, NCOA2-ETV4, ETV4-AHRR, P4HA2-TBCK, and TBCK-P4HA2 resulting from the translocations t(5;8;17)(p15;q13;q21) and t(4;5)(q24;q31) in a soft tissue angiofibroma.
Oncol Rep. 2016; 36(5):2455-2462 [PubMed] Free Access to Full Article Related Publications
We present an angiofibroma of soft tissue with the karyotype 46,XY,t(4;5)(q24;q31),t(5;8;17)(p15;q13;q21)[8]/46,XY,t(1;14)(p31;q32)[2]/46,XY[3]. RNA‑sequencing showed that the t(4;5)(q24;q31) resulted in recombination of the genes TBCK on 4q24 and P4HA2 on 5q31.1 with generation of an in‑frame TBCK‑P4HA2 and the reciprocal but out‑of‑frame P4HA2‑TBCK fusion transcripts. The putative TBCK‑P4HA2 protein would contain the kinase, the rhodanese‑like domain, and the Tre‑2/Bub2/Cdc16 (TBC) domains of TBCK together with the P4HA2 protein which is a component of the prolyl 4‑hydroxylase. The t(5;8;17)(p15;q13;q21) three‑way chromosomal translocation targeted AHRR (on 5p15), NCOA2 (on 8q13), and ETV4 (on 17q21) generating the in‑frame fusions AHRR‑NCOA2 and NCOA2‑ETV4 as well as an out‑of‑frame ETV4‑AHRR transcript. In the AHRR‑NCOA2 protein, the C‑terminal part of AHRR is replaced by the C‑terminal part of NCOA2 which contains two activation domains. The NCOA2‑ETV4 protein would contain the helix‑loop‑helix, PAS_9 and PAS_11, CITED domains, the SRC‑1 domain of NCOA2 and the ETS DNA‑binding domain of ETV4. No fusion gene corresponding to t(1;14)(p31;q32) was found. Our findings indicate that, in spite of the recurrence of AHRR‑NCOA2 in angiofibroma of soft tissue, additional genetic events (or fusion genes) might be required for the development of this tumor.

Minchenko DO, Riabovol OO, Tsymbal DO, et al.
Inhibition of IRE1 signaling affects the expression of genes encoded glucocorticoid receptor and some related factors and their hypoxic regulation in U87 glioma cells.
Endocr Regul. 2016; 50(3):127-36 [PubMed] Related Publications
OBJECTIVE: The aim of the present investigation was to examine the effect of inhibition of endoplasmic reticulum stress signaling, mediated by IRE1 (inositol requiring enzyme 1), which is a central mediator of the unfolded protein response on the expression of genes encoding glucocorticoid receptor (NR3C1) and some related proteins (SGK1, SGK3, NCOA1, NCOA2, ARHGAP35, NNT) and their hypoxic regulation in U87 glioma cells for evaluation of their possible significance in the control of the glioma growth.
METHODS: The expression of NR3C1,SGK1,SGK3, NCOA1, NCOA2, ARHGAP35, and NNT genes in U87 glioma cells, transfected by empty vector pcDNA3.1 (control) and cells without IRE1 signaling enzyme function (transfected by dnIRE1) upon hypoxia, was studied by quantitative polymerase chain reaction.
RESULTS: Inhibition of IRE1 signaling enzyme function up-regulates the expression of NR3C1, SGK1, NCOA1, NCOA2, ARHGAP35, and NNT genes in U87 glioma cells in comparison with the control glioma cells, with more significant changes for NR3C1, SGK1, and NNT genes. At the same time, the expression of SGK3 gene is strongly down-regulated in glioma cells upon inhibition of IRE1. We have also shown that hypoxia increases the expression of NR3C1, SGK1, NCOA2, ARHGAP35, and NNT genes but decreases SGK3 and NCOA1 genes expression in control glioma cells. Moreover, the inhibition of both enzymatic activities (kinase and endoribonuclease) of IRE1 in U87 glioma cells enhances the eff ect of hypoxia on the expression of SGK1, SGK3, and NNT genes, but decreases the sensitivity of NR3C1 gene to hypoxic condition. Furthermore, the expression of NCOA1 gene is resistant to hypoxia in control glioma cells, but NCOA2 and ARHGAP35 genes are resistant to this condition in glioma cells without functional activity of IRE1 signaling enzyme.
CONCLUSIONS: Results of this investigation demonstrate that inhibition of IRE1 signaling enzyme function affects the expression of NR3C1, SGK1, SGK3, NCOA1, NCOA2, ARHGAP35, and NNT genes in U87 glioma cells in gene specific manner and that all these genes are regulated by hypoxia preferentially through IRE1 signaling pathway of the endoplasmic reticulum stress.

Fritchie KJ, Jin L, Wang X, et al.
Fusion gene profile of biphenotypic sinonasal sarcoma: an analysis of 44 cases.
Histopathology. 2016; 69(6):930-936 [PubMed] Related Publications
AIMS: Biphenotypic sinonasal sarcoma (SNS) is a locally aggressive tumour that occurs in the sinonasal region. PAX3-MAML3 has recently been identified as a recurrent fusion gene event in this entity; however, a subset of tumours harbour alternative PAX3 rearrangement without the involvement of MAML3. In this study we sought to characterize the molecular profile of a large series of cases, with a special emphasis on tumours with alternative fusions.
METHODS AND RESULTS: Forty-four examples of SNS were screened by fluorescence in-situ hybridization and reverse transcription polymerase chain reaction to better characterize its molecular profile and identify potential novel fusion genes. Twenty-four were positive for PAX3-MAML3 (55%), 15 showed rearrangements of PAX3 without MAML3 involvement (34%), one showed rearrangement of MAML3 without PAX3 involvement, and four were negative for the involvement of either gene (9%). Among 15 cases with PAX3 involvement only, three were found to harbour PAX3-FOXO1. Two of these cases arose in the nasal cavities of female patients (aged 31 and 47 years), and one showed bilateral involvement of the nasal cavities of a 35-year-old male. A fourth case involved the skull base of a 47-year-old male, and was positive for PAX3-NCOA1. Patients with fusion-negative tumours were slightly older.
CONCLUSION: More than half of the SNSs in this series were positive for PAX3-MAML3. However, a subset of tumours may harbour alternative PAX3 fusion genes or show no involvement of PAX3. Except for a possible weak association between age and molecular profile, the overall morphological and immunophenotypic features of all cases seem to be similar. Because of the rarity of these tumours, the impact of the molecular profile on the clinical course of these tumours remains to be determined.

Swierniak M, Pfeifer A, Stokowy T, et al.
Somatic mutation profiling of follicular thyroid cancer by next generation sequencing.
Mol Cell Endocrinol. 2016; 433:130-7 [PubMed] Related Publications
The molecular etiology of follicular thyroid tumors is largely unknown, rendering the diagnostics of these tumors challenging. The somatic alterations present in these tumors apart from RAS gene mutations and PAX8/PPARG translocations are not well described. To evaluate the profile of somatic alteration in follicular thyroid tumors, a total of 82 thyroid tissue samples derived from 48 patients were subjected to targeted Illumina HiSeq next generation sequencing of 372 cancer-related genes. New somatic alterations were identified in oncogenes (MDM2, FLI1), transcription factors and repressors (MITF, FLI1, ZNF331), epigenetic enzymes (KMT2A, NSD1, NCOA1, NCOA2), and protein kinases (JAK3, CHEK2, ALK). Single nucleotide and large structural variants were most and least frequently identified, respectively. A novel translocation in DERL/COX6C was detected. Many somatic alterations in non-coding gene regions with high penetrance were observed. Thus, follicular thyroid tumor somatic alterations exhibit complex patterns. Most tumors contained distinct somatic alterations, suggesting previously unreported heterogeneity.

Luef B, Handle F, Kharaishvili G, et al.
The AR/NCOA1 axis regulates prostate cancer migration by involvement of PRKD1.
Endocr Relat Cancer. 2016; 23(6):495-508 [PubMed] Related Publications
Due to the urgent need for new prostate cancer (PCa) therapies, the role of androgen receptor (AR)-interacting proteins should be investigated. In this study we aimed to address whether the AR coactivator nuclear receptor coactivator 1 (NCOA1) is involved in PCa progression. Therefore, we tested the effect of long-term NCOA1 knockdown on processes relevant to metastasis formation. [(3)H]-thymidine incorporation assays revealed a reduced proliferation rate in AR-positive MDA PCa 2b and LNCaP cells upon knockdown of NCOA1, whereas AR-negative PC3 cells were not affected. Furthermore, Boyden chamber assays showed a strong decrease in migration and invasion upon NCOA1 knockdown, independently of the cell line's AR status. In order to understand the mechanistic reasons for these changes, transcriptome analysis using cDNA microarrays was performed. Protein kinase D1 (PRKD1) was found to be prominently up-regulated by NCOA1 knockdown in MDA PCa 2b, but not in PC3 cells. Inhibition of PRKD1 reverted the reduced migratory potential caused by NCOA1 knockdown. Furthermore, PRKD1 was negatively regulated by AR. Immunohistochemical staining of PCa patient samples revealed a strong increase in NCOA1 expression in primary tumors compared with normal prostate tissue, while no final conclusion could be drawn for PRKD1 expression in tumor specimens. Thus, our findings directly associate the AR/NCOA1 complex with PRKD1 regulation and cellular migration and support the concept of therapeutic inhibition of NCOA1 in PCa.

Obeid JP, Zafar N, El Hokayem J
Steroid Hormone Receptor Coregulators in Endocrine Cancers.
IUBMB Life. 2016; 68(7):504-15 [PubMed] Related Publications
Coregulators span a broad and extensive domain in modulating cellular transcriptional activity. Studies have established a dynamic role for such coregulators in various endocrine cancers. Steroid hormone receptors (SHRs) play a pivotal role in such endocrine cancers, and interact abundantly with transcriptional coregulators in altering gene expression. Several families of coregulators have implications in propagating the development, progression and invasion of breast, prostate, and other hormone-responsive cancers. This mini-review aims to discuss different classes of coregulators involved in endocrine cancers and highlight unique information regarding each family with relevance to mechanism, intervention, and novel directions being investigated. © 2016 IUBMB Life, 68(7):504-515, 2016.

Yang YC, Banuelos CA, Mawji NR, et al.
Targeting Androgen Receptor Activation Function-1 with EPI to Overcome Resistance Mechanisms in Castration-Resistant Prostate Cancer.
Clin Cancer Res. 2016; 22(17):4466-77 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Persistent androgen receptor (AR) transcriptional activity is clinically evident in castration-resistant prostate cancer (CRPC). Therefore, AR remains as a viable therapeutic target for CRPC. All current hormonal therapies target the C-terminus ligand-binding domain (LBD) of AR. By using EPI to target AR activation function-1 (AF-1), in the N-terminal domain that is essential for AR transactivation, we evaluate the ability of EPI to overcome several clinically relevant AR-related mechanisms of resistance.
EXPERIMENTAL DESIGN: To study the effect of EPI on AR transcriptional activity against overexpressed coactivators, such as SRC1-3 and p300, luciferase reporter assays were performed using LNCaP cells. AR-negative COS-1 cells were employed for reporter assays to examine whether the length of polyglutamine tract affects inhibition by EPI. The effect of EPI on constitutively active AR splice variants was studied in LNCaP95 cells, which express AR-V7 variant. To evaluate the effect of EPI on the proliferation of LNCaP95 cells, we performed in vitro BrdUrd incorporation assay and in vivo studies using xenografts in mice.
RESULTS: EPI effectively overcame several molecular alterations underlying aberrant AR activity, including overexpressed coactivators, AR gain-of-function mutations, and constitutively active AR-V7. EPI inhibited AR transcriptional activity regardless of the length of polyglutamine tract. Importantly, EPI significantly inhibited the in vitro and in vivo proliferation of LNCaP95 prostate cancer cells, which are androgen independent and enzalutamide resistant.
CONCLUSIONS: These findings support EPI as a promising therapeutic agent to treat CRPC, particularly against tumors driven by constitutively active AR splice variants that are resistant to LBD-targeting drugs. Clin Cancer Res; 22(17); 4466-77. ©2016 AACRSee related commentary by Sharp et al., p. 4280.

Glass S, Phan A, Williams JN, et al.
Integrating understanding of epidemiology and genomics in B-cell non-Hodgkin lymphoma as a pathway to novel management strategies.
Discov Med. 2016; 21(115):181-8 [PubMed] Free Access to Full Article Related Publications
Non-Hodgkin lymphomas include a biologically and clinically heterogeneous group of cancers distinguished by genetics, histology, and treatment outcomes. New discoveries regarding the genomic alterations and epidemiological exposures associated with these lymphomas have enhanced our understanding of factors that contribute to lymphomagenesis for specific subtypes. We explore the impact of normal B-cell biology engineered for recognizing a wide variety of antigens on the development of specific lymphoma subtypes, review lymphoma genetics, and examine the epidemiology of B-cell NHLs including recent investigations of risk factors for particular lymphoma subtypes based on large pooled analyses. Burkitt lymphoma, an aggressive form of B-cell NHL involving translocation of the MYC gene and an immunoglobulin gene has been associated with a history of eczema, hepatitis C, and occupation as a cleaner. Increased risk of diffuse large B-cell lymphoma has been associated with increased young adult body mass index, history of B-cell-activating autoimmune diseases, hepatitis C, and several single nucleotide variants involving the human leukocyte antigen (HLA) region of chromosome 6 and non-HLA loci near EXOC2, PVT1, MYC, and NCOA1. Tumor sequencing studies suggest that multiple pathways are involved in the development of DLBCL. Additional studies of epidemiological exposures, genome wide associations, and tumor sequencing in follicular, lymphoplasmacytic, marginal zone, and mantle cell lymphoma demonstrate overlapping areas of increased risk factors and unique factors for specific subtypes. Integrating these findings is important for constructing comprehensive models of NHL pathogenesis, which could yield novel targets for therapy and strategies for lymphoma prevention in certain populations.

Wang J, Zou JX, Xue X, et al.
ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer.
Nat Med. 2016; 22(5):488-96 [PubMed] Free Access to Full Article Related Publications
The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice. Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa.

Liu X, Li H, Rajurkar M, et al.
Tead and AP1 Coordinate Transcription and Motility.
Cell Rep. 2016; 14(5):1169-1180 [PubMed] Free Access to Full Article Related Publications
The Tead family transcription factors are the major intracellular mediators of the Hippo-Yap pathway. Despite the importance of Hippo signaling in tumorigenesis, Tead-dependent downstream oncogenic programs and target genes in cancer cells remain poorly understood. Here, we characterize Tead4-mediated transcriptional networks in a diverse range of cancer cells, including neuroblastoma, colorectal, lung, and endometrial carcinomas. By intersecting genome-wide chromatin occupancy analyses of Tead4, JunD, and Fra1/2, we find that Tead4 cooperates with AP1 transcription factors to coordinate target gene transcription. We find that Tead-AP1 interaction is JNK independent but engages the SRC1-3 co-activators to promote downstream transcription. Furthermore, we show that Tead-AP1 cooperation regulates the activity of the Dock-Rac/CDC42 module and drives the expression of a unique core set of target genes, thereby directing cell migration and invasion. Together, our data unveil a critical regulatory mechanism underlying Tead- and AP1-controlled transcriptional and functional outputs in cancer cells.

Pavón MA, Parreño M, Téllez-Gabriel M, et al.
CKMT1 and NCOA1 expression as a predictor of clinical outcome in patients with advanced-stage head and neck squamous cell carcinoma.
Head Neck. 2016; 38 Suppl 1:E1392-403 [PubMed] Related Publications
BACKGROUND: We studied the association between the expression of a subset of previously identified genes and clinical outcome in patients with head and neck cancer.
METHODS: We analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) the expression of 89 genes in tumor biopsies from stage III to IVa/b chemotherapy treated patients (n = 46). Two additional cohorts analyzed by RNAseq (The Cancer Genome Atlas [TCGA] project; n = 371) or immunohistochemistry (IHC; n = 73) were used to validate results.
RESULTS: Thirty genes were associated with local-recurrence or progression-free survival. The best multi-gene decision-tree model to predict local recurrence included nuclear receptor coactivator 1 (NCOA1) and serum-amyloid A2 (SAA2) expression, whereas the best model to predict disease recurrence included creatine kinase mitochondrial 1 (CKMT1) and metal-regulatory transcription factor 1 (MTF1). Both models were associated with cancer-specific survival. Results were confirmed analyzing the RNAseq data included in the TCGA project. CKMT1 and NCOA1 were identified as independent risk factors for survival in an independent cohort analyzed by immunohistochemistry.
CONCLUSION: CKMT1 and NCOA1 expression has prognostic significance in advanced-stage head and neck carcinoma. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1392-E1403, 2016.

Villagran MA, Gutierrez-Castro FA, Pantoja DF, et al.
Bone stroma-derived cells change coregulators recruitment to androgen receptor and decrease cell proliferation in androgen-sensitive and castration-resistant prostate cancer cells.
Biochem Biophys Res Commun. 2015; 467(4):1039-45 [PubMed] Related Publications
Prostate cancer (CaP) bone metastasis is an early event that remains inactive until later-stage progression. Reduced levels of circulating androgens, due to andropause or androgen deprivation therapies, alter androgen receptor (AR) coactivator expression. Coactivators shift the balance towards enhanced AR-mediated gene transcription that promotes progression to androgen-resistance. Disruptions in coregulators may represent a molecular switch that reactivates latent bone metastasis. Changes in AR-mediated transcription in androgen-sensitive LNCaP and androgen-resistant C4-2 cells were analyzed for AR coregulator recruitment in co-culture with Saos-2 and THP-1. The Saos-2 cell line derived from human osteosarcoma and THP-1 cell line representing human monocytes were used to display osteoblast and osteoclast activity. Increased AR activity in androgen-resistant C4-2 was due to increased AR expression and SRC1/TIF2 recruitment and decreased SMRT/NCoR expression. AR activity in both cell types was decreased over 90% when co-cultured with Saos-2 or THP-1 due to dissociation of AR from the SRC1/TIF2 and SMRT/NCoR coregulators complex, in a ligand-dependent and cell-type specific manner. In the absence of androgens, Saos-2 decreased while THP-1 increased proliferation of LNCaP cells. In contrast, both Saos-2 and THP-1 decreased proliferation of C4-2 in absence and presence of androgens. Global changes in gene expression from both CaP cell lines identified potential cell cycle and androgen regulated genes as mechanisms for changes in cell proliferation and AR-mediated transactivation in the context of bone marrow stroma cells.

Esber N, Le Billan F, Resche-Rigon M, et al.
Ulipristal Acetate Inhibits Progesterone Receptor Isoform A-Mediated Human Breast Cancer Proliferation and BCl2-L1 Expression.
PLoS One. 2015; 10(10):e0140795 [PubMed] Free Access to Full Article Related Publications
The progesterone receptor (PR) with its isoforms and ligands are involved in breast tumorigenesis and prognosis. We aimed at analyzing the respective contribution of PR isoforms, PRA and PRB, in breast cancer cell proliferation in a new estrogen-independent cell based-model, allowing independent PR isoforms analysis. We used the bi-inducible human breast cancer cell system MDA-iPRAB. We studied the effects and molecular mechanisms of action of progesterone (P4) and ulipristal acetate (UPA), a new selective progesterone receptor modulator, alone or in combination. P4 significantly stimulated MDA-iPRA expressing cells proliferation. This was associated with P4-stimulated expression of the anti-apoptotic factor BCL2-L1 and enhanced recruitment of PRA, SRC-1 and RNA Pol II onto the +58 kb PR binding motif of the BCL2-L1 gene. UPA decreased cell proliferation and repressed BCL2-L1 expression in the presence of PRA, correlating with PRA and SRC1 but not RNA Pol II recruitment. These results bring new information on the mechanism of action of PR ligands in controlling breast cancer cell proliferation through PRA in an estrogen independent model. Evaluation of PR isoforms ratio, as well as molecular signature studies based on PRA target genes could be proposed to facilitate personalized breast cancer therapy. In this context, UPA could be of interest in endocrine therapy. Further confirmation in the clinical setting is required.

Huang SC, Ghossein RA, Bishop JA, et al.
Novel PAX3-NCOA1 Fusions in Biphenotypic Sinonasal Sarcoma With Focal Rhabdomyoblastic Differentiation.
Am J Surg Pathol. 2016; 40(1):51-9 [PubMed] Free Access to Full Article Related Publications
Sarcomas arising in the sinonasal region are uncommon and encompass a wide variety of tumor types, including the newly described biphenotypic sinonasal sarcoma (BSNS), which is characterized by a monomorphic spindle cell proliferation with dual neural and myogenic phenotypes. Most BSNSs harbor a pathognomonic PAX3-MAML3 fusion driven by t(2;4)(q35;q31.1), whereas the alternative fusion partner gene remains unidentified in a subset of PAX3-rearranged cases. As NCOA1 on 2p23 is a known partner in PAX3-related fusions in other tumor types (ie, alveolar rhabdomyosarcoma), we investigated its status by fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction assays in 2 BSNS cases showing only PAX3 gene rearrangements. Novel PAX3-NCOA1 fusions were identified in these 2 index cases showing an inv(2)(q35p23) by FISH and confirmed by reverse transcription polymerase chain reaction. Five additional BSNS cases with typical morphology were studied by FISH, revealing a PAX3-MAML3 fusion in 4 cases and only PAX3 rearrangement in the remaining case without abnormalities in MAML3 or NCOA1 gene. Except for 1 case with surface ulceration, all other tumors lacked increased mitotic activity or necrosis, and all cases immunohistochemically coexpressed S100 protein and actin, but lacked SOX10 reactivity. Interestingly, the 2 PAX3-NCOA1-positive cases showed desmin reactivity and displayed a small component of rhabdomyoblastic cells, which were not seen in the more common PAX3-MAML3 fusion cases. In conclusion, we report a novel PAX3-NCOA1 fusion in BSNS, which appears to be associated with focal rhabdomyoblastic differentiation and should be distinguished from PAX3-NCOA1-positive alveolar rhabdomyosarcoma or malignant Triton tumor. SOX10 immunohistochemistry is a useful marker in distinguishing BSNS from peripheral nerve sheath tumors.

Qin L, Xu Y, Xu Y, et al.
NCOA1 promotes angiogenesis in breast tumors by simultaneously enhancing both HIF1α- and AP-1-mediated VEGFa transcription.
Oncotarget. 2015; 6(27):23890-904 [PubMed] Free Access to Full Article Related Publications
Nuclear receptor coactivator 1 (NCOA1) is overexpressed in a subset of breast cancer and its increased expression positively correlates with disease recurrence and metastasis. Although NCOA1 is known to promote breast cancer metastasis through working with multiple transcription factors to upregulate the expression of Twist1, ITGA5, CSF-1, SDF1 and CXCR4, the role of NCOA1 in breast tumor angiogenesis has not been investigated. In this study, we found that the microvascular density (MVD) was significantly decreased and increased in Ncoa1-knockout and NCOA1-overexpressing mammary tumors, respectively, in several breast cancer mouse models. Knockout or knockdown of NCOA1 in breast cancer cell lines also markedly compromised their capability to induce angiogenesis in Matrigel plugs embedded subcutaneously in mice, while this compromised capability could be rescued by VEGFa treatment. At the molecular level, NCOA1 upregulates VEGFa expression in both mouse mammary tumors and cultured breast cancer cells, and it does so by associating with both c-Fos, which is recruited to the AP-1 site at bp -938 of the VEGFa promoter, and HIF1α, which is recruited to the HIF1α-binding element at bp -979 of the VEGFa promoter, to enhance VEGFa transcription. In 140 human breast tumors, high NCOA1 protein correlates with high MVD and patients with both high NCOA1 and high MVD showed significantly shorter survival time. In summary, this study revealed a novel mechanism that NCOA1 potentiates breast cancer angiogenesis through upregulating HIF1α and AP-1-mediated VEGFa expression, which reinforces the rational of targeting NCOA1 in controlling breast cancer progression and metastasis.

Sibbesen NA, Kopp KL, Litvinov IV, et al.
Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma.
Oncotarget. 2015; 6(24):20555-69 [PubMed] Free Access to Full Article Related Publications
Aberrant activation of Janus kinase-3 (Jak3) and its key down-stream effectors, Signal Transducer and Activator of Transcription-3 (STAT3) and STAT5, is a key feature of malignant transformation in cutaneous T-cell lymphoma (CTCL). However, it remains only partially understood how Jak3/STAT activation promotes lymphomagenesis. Recently, non-coding microRNAs (miRNAs) have been implicated in the pathogenesis of this malignancy. Here, we show that (i) malignant T cells display a decreased expression of a tumor suppressor miRNA, miR-22, when compared to non-malignant T cells, (ii) STAT5 binds the promoter of the miR-22 host gene, and (iii) inhibition of Jak3, STAT3, and STAT5 triggers increased expression of pri-miR-22 and miR-22. Curcumin, a nutrient with anti-Jak3 activity and histone deacetylase inhibitors (HDACi) also trigger increased expression of pri-miR-22 and miR-22. Transfection of malignant T cells with recombinant miR-22 inhibits the expression of validated miR-22 targets including NCoA1, a transcriptional co-activator in others cancers, as well as HDAC6, MAX, MYCBP, PTEN, and CDK2, which have all been implicated in CTCL pathogenesis. In conclusion, we provide the first evidence that de-regulated Jak3/STAT3/STAT5 signalling in CTCL cells represses the expression of the gene encoding miR-22, a novel tumor suppressor miRNA.

Andres SA, Bickett KE, Alatoum MA, et al.
Interaction between smoking history and gene expression levels impacts survival of breast cancer patients.
Breast Cancer Res Treat. 2015; 152(3):545-56 [PubMed] Related Publications
In contrast to studies focused on cigarette smoking and risk of breast cancer occurrence, this study explored the influence of smoking on breast cancer recurrence and progression. The goal was to evaluate the interaction between smoking history and gene expression levels on recurrence and overall survival of breast cancer patients. Multivariable Cox proportional hazards models were fitted for 48 cigarette smokers, 50 non-smokers, and the total population separately to determine which gene expressions and gene expression/cigarette usage interaction terms were significant in predicting overall and disease-free survival in breast cancer patients. Using methods similar to Andres et al. (BMC Cancer 13:326, 2013a; Horm Cancer 4:208-221, 2013b), multivariable analyses revealed CENPN, CETN1, CYP1A1, IRF2, LECT2, and NCOA1 to be important predictors for both breast carcinoma recurrence and mortality among smokers. Additionally, COMT was important for recurrence, and NAT1 and RIPK1 were important for mortality. In contrast, only IRF2, CETN1, and CYP1A1 were significant for disease recurrence and mortality among non-smokers, with NAT2 additionally significant for survival. Analysis of interaction between smoking status and gene expression values using the combined samples revealed significant interactions between smoking status and CYP1A1, LECT2, and CETN1. Signatures consisting of 7-8 genes were highly predictive for breast cancer recurrence and overall survival among smokers, with median C-index values of 0.8 and 0.73 for overall survival and recurrence, respectively. In contrast, median C-index values for non-smokers was only 0.59. Hence, significant interactions between gene expression and smoking status can play a key role in predicting breast cancer patient outcomes.

Ayala G, Frolov A, Chatterjee D, et al.
Expression of ERG protein in prostate cancer: variability and biological correlates.
Endocr Relat Cancer. 2015; 22(3):277-87 [PubMed] Free Access to Full Article Related Publications
Prostate cancer is the second leading cause of cancer-related death of men in the USA. The TMPRSS2/ERG (T/E) fusion gene is present in approximately 50% of prostate cancers and promotes tumor progression in vivo. The presence of the T/E fusion gene is strongly associated with the expression of ERG protein, but emerging evidence indicates a significant interfocal and intrafocal variability in the levels of ERG protein expression. We therefore analyzed ERG protein expression by image analysis to objectively quantitate the extent of such heterogeneity, and confirmed significant interfocal and intrafocal variability of ERG protein expression levels in cancer expressing ERG. To define the pathways associated with ERG and its variable expression in prostate cancer, we have analyzed the correlations of ERG expression, as evaluated by immunohistochemistry, with 46 key proteins associated with signal transduction, transcriptional control, and other processes using a large tissue microarray with more than 500 prostate cancers. We found a significant correlation of ERG expression with the markers of activation of the PI3K, MYC, and NFκB pathways, which had previously been linked directly or indirectly to ERG expression. We have also identified significant correlations with novel proteins that have not been previously linked to ERG expression, including serum response factor, the p160 coactivator SRC1, and Sprouty1. Notably, SKP2 only correlated with a high level of ERG protein expression. Thus ERG expression is variable in prostate cancer and is associated with activation of multiple pathways and proteins including several potentially targetable pathways.

Yoo HM, Kang SH, Kim JY, et al.
Modification of ASC1 by UFM1 is crucial for ERα transactivation and breast cancer development.
Mol Cell. 2014; 56(2):261-274 [PubMed] Related Publications
Biological roles for UFM1, a ubiquitin-like protein, are largely unknown, and therefore we screened for targets of ufmylation. Here we show that ufmylation of the nuclear receptor coactivator ASC1 is a key step for ERα transactivation in response to 17β-estradiol (E2). In the absence of E2, the UFM1-specific protease UfSP2 was bound to ASC1, which maintains ASC1 in a nonufmylated state. In the presence of E2, ERα bound ASC1 and displaced UfSP2, leading to ASC1 ufmylation. Polyufmylation of ASC1 enhanced association of p300, SRC1, and ASC1 at promoters of ERα target genes. ASC1 overexpression or UfSP2 knockdown promoted ERα-mediated tumor formation in vivo, which could be abrogated by treatment with the anti-breast cancer drug tamoxifen. In contrast, expression of ufmylation-deficient ASC1 mutant or knockdown of the UFM1-activating E1 enzyme UBA5 prevented tumor growth. These findings establish a role for ASC1 ufmylation in breast cancer development by promoting ERα transactivation.

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