Gene Summary

Gene:EP300; E1A binding protein p300
Aliases: p300, KAT3B, MKHK2, RSTS2
Summary:This gene encodes the adenovirus E1A-associated cellular p300 transcriptional co-activator protein. It functions as histone acetyltransferase that regulates transcription via chromatin remodeling and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. This gene has also been identified as a co-activator of HIF1A (hypoxia-inducible factor 1 alpha), and thus plays a role in the stimulation of hypoxia-induced genes such as VEGF. Defects in this gene are a cause of Rubinstein-Taybi syndrome and may also play a role in epithelial cancer. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:histone acetyltransferase p300
Source:NCBIAccessed: 29 August, 2019


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 29 August 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.

Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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

Entity Topic PubMed Papers
Rubinstein-Taybi SyndromeEP300 mutation in Rubinstein-Taybi Syndrome
Rubinstein-Taybi Syndrome is an autosomal dominant chromosomal disorder characterized by mental retardation, broad thumbs, and webbing of fingers and toes. Individuals with RTS have an increased risk of brain tumors and certain other cancers.
View Publications53
Breast CancerEP300 and Breast Cancer View Publications32
Lung CancerEP300 and Lung Cancer View Publications27
Ovarian CancerEP300 and Ovarian Cancer View Publications10
Esophageal CancerEP300 and Esophageal CancerPrognostic View Publications9
Stomach CancerEP300 and Stomach Cancer View Publications6

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

Latest Publications: EP300 (cancer-related)

Kishore C, Sundaram S, Karunagaran D
Vitamin K3 (menadione) suppresses epithelial-mesenchymal-transition and Wnt signaling pathway in human colorectal cancer cells.
Chem Biol Interact. 2019; 309:108725 [PubMed] Related Publications
Tumor recurrence and metastasis decrease the survival rate of colorectal cancer (CRC) patients. Menadione reduces the numbers and incidences of 1,2-dimethylhydrazine induced colon tumors in mouse but the mechanism of anticancer activity of menadione in colorectal cancer is not very clear. Since Wnt signaling is constitutively active in CRC and it aggravates the epithelial mesenchymal transition (EMT), the regulation of EMT and Wnt signaling by menadione (vitamin K3) was investigated in CRC cells. Menadione showed cytotoxicity against human CRC cells (SW480 and SW620) and human primary colon cancer cells but was relatively ineffective against the cells from human normal colon (CRL-1790) and human primary colon epithelial cells. Menadione suppressed invasion, migration and epithelial-mesenchymal transition in human CRC cells by upregulating the expression of E-cadherin (CDH1), ZO-1 and downregulating that of N-cadherin (CDH2), Vimentin (VIM), ZEB1, MMP2 and MMP9. Menadione decreased TOPFlash/FOPFlash luciferase activity and expression of several downstream targets of Wnt signaling and coactivators such as β-catenin (CTNNB1), TCF7L2, Bcl9l, p300 (EP300) and cyclin D1 (CCND1) was suppressed. Menadione induced differentiation and increased apoptotic cell population in SubG0 phase of cell cycle in SW480 and SW620 cells. The ability of menadione to suppress EMT, migration, invasion, Wnt signaling, cell proliferation and induce Sub G0 arrest, highlights its potential to be considered for intensive preclinical and clinical investigation in CRC.

Ando M, Saito Y, Xu G, et al.
Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers.
Nat Commun. 2019; 10(1):2188 [PubMed] Free Access to Full Article Related Publications
Although promoter-associated CpG islands have been established as targets of DNA methylation changes in cancer, previous studies suggest that epigenetic dysregulation outside the promoter region may be more closely associated with transcriptional changes. Here we examine DNA methylation, chromatin marks, and transcriptional alterations to define the relationship between transcriptional modulation and spatial changes in chromatin structure. Using human papillomavirus-related oropharyngeal carcinoma as a model, we show aberrant enrichment of repressive H3K9me3 at the transcriptional start site (TSS) with methylation-associated, tumor-specific gene silencing. Further analysis identifies a hypermethylated subtype which shows a functional convergence on MYC targets and association with CREBBP/EP300 mutation. The tumor-specific shift to transcriptional repression associated with DNA methylation at TSSs was confirmed in multiple tumor types. Our data may show a common underlying epigenetic dysregulation in cancer associated with broad enrichment of repressive chromatin marks and aberrant DNA hypermethylation at TSSs in combination with MYC network activation.

Holding AN, Giorgi FM, Donnelly A, et al.
VULCAN integrates ChIP-seq with patient-derived co-expression networks to identify GRHL2 as a key co-regulator of ERa at enhancers in breast cancer.
Genome Biol. 2019; 20(1):91 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: VirtUaL ChIP-seq Analysis through Networks (VULCAN) infers regulatory interactions of transcription factors by overlaying networks generated from publicly available tumor expression data onto ChIP-seq data. We apply our method to dissect the regulation of estrogen receptor-alpha activation in breast cancer to identify potential co-regulators of the estrogen receptor's transcriptional response.
RESULTS: VULCAN analysis of estrogen receptor activation in breast cancer highlights the key components of the estrogen receptor complex alongside a novel interaction with GRHL2. We demonstrate that GRHL2 is recruited to a subset of estrogen receptor binding sites and regulates transcriptional output, as evidenced by changes in estrogen receptor-associated eRNA expression and stronger estrogen receptor binding at active enhancers after GRHL2 knockdown.
CONCLUSIONS: Our findings provide new insight into the role of GRHL2 in regulating eRNA transcription as part of estrogen receptor signaling. These results demonstrate VULCAN, available from Bioconductor, as a powerful predictive tool.

Wu P, Cai J, Chen Q, et al.
Lnc-TALC promotes O
Nat Commun. 2019; 10(1):2045 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules implicated in diverse biological processes, including therapeutic resistance. However, the mechanisms underlying lncRNA-mediated temozolomide (TMZ) resistance in glioblastoma (GBM) remain largely unknown. To illustrate the role of lncRNA in TMZ resistance, we induce TMZ-resistant GBM cells, perform a lncRNA microarray of the parental and TMZ-resistant cells, and find an unreported lncRNA in GBM, lnc-TALC (temozolomide-associated lncRNA in glioblastoma recurrence), correlated with TMZ resistance via competitively binding miR-20b-3p to facilitate c-Met expression. A phosphorylated AKT/FOXO3 axis regulated lnc-TALC expression in TMZ-resistant GBM cells. Furthermore, lnc-TALC increased MGMT expression by mediating the acetylation of H3K9, H3K27 and H3K36 in MGMT promoter regions through the c-Met/Stat3/p300 axis. In clinical patients, lnc-TALC is required for TMZ resistance and GBM recurrence. Our results reveal that lnc-TALC in GBM could serve as a therapeutic target to overcome TMZ resistance, enhancing the clinical benefits of TMZ chemotherapy.

Cocchiola R, Rubini E, Altieri F, et al.
STAT3 Post-Translational Modifications Drive Cellular Signaling Pathways in Prostate Cancer Cells.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
STAT3 is an oncoprotein overexpressed in different types of tumors, including prostate cancer (PCa), and its activity is modulated by a variety of post-translational modifications (PTMs). Prostate cancer represents the most common cancer diagnosed in men, and each phase of tumor progression displays specific cellular conditions: inflammation is predominant in tumor's early stage, whereas oxidative stress is typical of clinically advanced PCa. The aim of this research is to assess the correspondence between the stimulus-specificity of STAT3 PTMs and definite STAT3-mediated transcriptional programs, in order to identify new suitable pharmacological targets for PCa treatment. Experiments were performed on less-aggressive LNCaP and more aggressive DU-145 cell lines, simulating inflammatory and oxidative-stress conditions. Cellular studies confirmed pY705-STAT3 as common denominator of all STAT3-mediated signaling. In addition, acK685-STAT3 was found in response to IL-6, whereas glutC328/542-STAT3 and pS727-STAT3 occurred upon tert-butyl hydroperoxyde (tBHP) treatment. Obtained results also provided evidence of an interplay between STAT3 PTMs and specific protein interactors such as P300 and APE1/Ref-1. In accordance with these outcomes, mRNA levels of STAT3-target genes seemed to follow the differing STAT3 PTMs. These results highlighted the role of STAT3 and its PTMs as drivers in the progression of PCa.

Lawrenson K, Song F, Hazelett DJ, et al.
Genome-wide association studies identify susceptibility loci for epithelial ovarian cancer in east Asian women.
Gynecol Oncol. 2019; 153(2):343-355 [PubMed] Related Publications
OBJECTIVE: Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women.
METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations.
RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10
CONCLUSION: While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.

Wang YQ, Jiang DM, Hu SS, et al.
Cancer Res. 2019; 79(14):3542-3556 [PubMed] Related Publications
Accumulating evidence suggests that long noncoding RNA (lncRNA) plays important regulatory roles in cancer biology. However, the involvement of lncRNA in colorectal carcinoma progression remains largely unknown, especially in colorectal carcinoma metastasis. In this study, we investigated the changes in lncRNA expression in colorectal carcinoma and identified a new lncRNA, the antisense transcript of SATB2 (

Tang W, Zhou W, Xiang L, et al.
The p300/YY1/miR-500a-5p/HDAC2 signalling axis regulates cell proliferation in human colorectal cancer.
Nat Commun. 2019; 10(1):663 [PubMed] Free Access to Full Article Related Publications
The biological role of miR-500a-5p has not yet been reported in the context of colorectal cancer (CRC). Here, we show that miR-500a-5p expression is decreased in CRC tissues compared with adjacent normal tissues. Low miR-500a-5p expression is associated with malignant progression. Moreover, transfection of CRC cells with miR-500a-5p induces G0/G1 cell cycle arrest and inhibits their growth and migration. Mechanistically, miR-500a-5p directly targets HDAC2 and inhibits HDAC2-mediated proliferation in CRC in nude mice. Furthermore, YY1 binds to the promoter of miR-500a-5p and negatively regulates its transcription. Restoration of miR-500a-5p expression is up-regulated via the p300/YY1/HDAC2 complex. Besides, therapeutic delivery of miR-500a-5p significantly suppresses tumour development in a xenograft tumour model and a HDAC2 inhibitor FK228-treated CRC model. Our studies demonstrate that miR-500a-5p functions as a tumour suppressor in CRC by targeting the p300/YY1/HDAC2 axis, which contributes to the development of and provides new potential candidates for CRC therapy.

Cuevas D, Valls J, Gatius S, et al.
Targeted sequencing with a customized panel to assess histological typing in endometrial carcinoma.
Virchows Arch. 2019; 474(5):585-598 [PubMed] Related Publications
The two most frequent types of endometrial cancer (EC) are endometrioid (EEC) and serous carcinomas (SC). Differential diagnosis between them is not always easy. A subset of endometrial cancers shows misleading microscopical features, which cause problems in differential diagnosis, and may be a good scenario for next-generation sequencing. Previous studies have assessed the usefulness of targeted sequencing with panels of generic cancer-associated genes in EC histological typing. Based on the analysis of TCGA (The Cancer Genome Atlas), EEC and SC have different mutational profiles. In this proof of principle study, we have performed targeted sequencing analysis with a customized panel, based on the TCGA mutational profile of EEC and SC, in a series of 24 tumors (16 EEC and 8 SC). Our panel comprised coding and non-coding sequences of the following genes: ABCC9, ARID1A, ARID5B, ATR, BCOR, CCND1, CDH19, CHD4, COL11A1, CSDE1, CSMD3, CTCF, CTNNB1, EP300, ERBB2, FBXW7, FGFR2, FOXA2, KLLN, KMT2B, KRAS, MAP3K4, MKI67, NRAS, PGAP3, PIK3CA, PIK3R1, PPP2R1A, PRPF18, PTEN, RPL22, SCARNA11, SIN3A, SMARCA4, SPOP, TAF1, TP53, TSPYL2, USP36, and WRAP53. Targeted sequencing validation by Sanger sequencing and immunohistochemistry was performed in a group of genes. POLE mutation status was assessed by Sanger sequencing. The most mutated genes were PTEN (93.7%), ARID1A (68.7%), PIK3CA (50%), and KMT2B (43.7%) for EEC, and TP53 (87.5%), PIK3CA (50%), and PPP2R1A (25%) for SC. Our panel allowed correct classification of all tumors in the two categories (EEC, SC). Coexistence of mutations in PTEN, ARID1A, and KMT2B was diagnostic of EEC. On the other hand, absence of PTEN, ARID1A, and KMT2B mutations in the presence of TP53 mutation was diagnostic of SC. This proof of concept study demonstrates the suitability of targeted sequencing with a customized endometrial cancer gene panel as an additional tool for confirming histological typing.

Fry EA, Inoue K
c-MYB and DMTF1 in Cancer.
Cancer Invest. 2019; 37(1):46-65 [PubMed] Article available free on PMC after 02/01/2020 Related Publications
The c-Myb gene encodes a transcription factor that regulates cell proliferation, differentiation, and apoptosis through protein-protein interaction and transcriptional regulation of signaling pathways. The protein is frequently overexpressed in human leukemias, breast cancers, and other solid tumors suggesting that it is a bona fide oncogene. c-MYB is often overexpressed by translocation in human tumors with t(6;7)(q23;q34) resulting in c-MYB-TCRβ in T cell ALL, t(X;6)(p11;q23) with c-MYB-GATA1 in acute basophilic leukemia, and t(6;9)(q22-23;p23-24) with c-MYB-NF1B in adenoid cystic carcinoma. Antisense oligonucleotides to c-MYB were developed to purge bone marrow cells to eliminate tumor cells in leukemias. Recently, small molecules that inhibit c-MYB activity have been developed to disrupt its interaction with p300. The Dmp1 (cyclin D binding myb-like protein 1; Dmtf1) gene was isolated through its virtue for binding to cyclin D2. It is a transcription factor that has a Myb-like repeat for DNA binding. The Dmtf1 protein directly binds to the Arf promoter for transactivation and physically interacts with p53 to activate the p53 pathway. The gene is hemizygously deleted in 35-42% of human cancers and is associated with longer survival. The significances of aberrant expression of c-MYB and DMTF1 proteins in human cancers and their clinical significances are discussed.

Gillison ML, Akagi K, Xiao W, et al.
Human papillomavirus and the landscape of secondary genetic alterations in oral cancers.
Genome Res. 2019; 29(1):1-17 [PubMed] Article available free on PMC after 02/01/2020 Related Publications
Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCCs) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCCs, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. In contrast, in HPV-negative OSCCs, T>C substitutions in the sequence context 5'-ATN-3' correlated with tobacco exposure. Universal expression of HPV

Fukuoka K, Kanemura Y, Shofuda T, et al.
Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors.
Acta Neuropathol Commun. 2018; 6(1):134 [PubMed] Article available free on PMC after 02/01/2020 Related Publications
Extensive molecular analyses of ependymal tumors have revealed that supratentorial and posterior fossa ependymomas have distinct molecular profiles and are likely to be different diseases. The presence of C11orf95-RELA fusion genes in a subset of supratentorial ependymomas (ST-EPN) indicated the existence of molecular subgroups. However, the pathogenesis of RELA fusion-negative ependymomas remains elusive. To investigate the molecular pathogenesis of these tumors and validate the molecular classification of ependymal tumors, we conducted thorough molecular analyses of 113 locally diagnosed ependymal tumors from 107 patients in the Japan Pediatric Molecular Neuro-Oncology Group. All tumors were histopathologically reviewed and 12 tumors were re-classified as non-ependymomas. A combination of RT-PCR, FISH, and RNA sequencing identified RELA fusion in 19 of 29 histologically verified ST-EPN cases, whereas another case was diagnosed as ependymoma RELA fusion-positive via the methylation classifier (68.9%). Among the 9 RELA fusion-negative ST-EPN cases, either the YAP1 fusion, BCOR tandem duplication, EP300-BCORL1 fusion, or FOXO1-STK24 fusion was detected in single cases. Methylation classification did not identify a consistent molecular class within this group. Genome-wide methylation profiling successfully sub-classified posterior fossa ependymoma (PF-EPN) into PF-EPN-A (PFA) and PF-EPN-B (PFB). A multivariate analysis using Cox regression confirmed that PFA was the sole molecular marker which was independently associated with patient survival. A clinically applicable pyrosequencing assay was developed to determine the PFB subgroup with 100% specificity using the methylation status of 3 genes, CRIP1, DRD4 and LBX2. Our results emphasized the significance of molecular classification in the diagnosis of ependymomas. RELA fusion-negative ST-EPN appear to be a heterogeneous group of tumors that do not fall into any of the existing molecular subgroups and are unlikely to form a single category.

MacFawn I, Wilson H, Selth LA, et al.
Grainyhead-like-2 confers NK-sensitivity through interactions with epigenetic modifiers.
Mol Immunol. 2019; 105:137-149 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Natural Killer (NK) cells suppress tumor initiation and metastasis. Most carcinomas are heterogeneous mixtures of epithelial, mesenchymal and hybrid tumor cells, but the relationships of these phenotypes to NK susceptibility are understood incompletely. Grainyhead-like-2 (GRHL2) is a master programmer of the epithelial phenotype, that is obligatorily down-regulated during experimentally induced Epithelial-Mesenchymal Transition (EMT). Here, we utilize GRHL2 re-expression to discover unifying molecular mechanisms that link the epithelial phenotype with NK-sensitivity. GRHL2 enhanced the expression of ICAM-1, augmenting NK-target cell synaptogenesis and NK killing of target cells. The expression of multiple interferon response genes, including ICAM1, anti-correlated with EMT. We identified two novel GRHL2-interacting proteins, the histone methyltransferases KMT2C and KMT2D. Mesenchymal-epithelial transition, NK-sensitization and ICAM-1 expression were promoted by GRHL2-KMT2C/D interactions and by GRHL2 inhibition of p300, revealing novel and potentially targetable epigenetic mechanisms connecting the epithelial phenotype with target cell susceptibility to NK killing.

Liu W, Xiao H, Wu S, et al.
MAP9 single nucleotide polymorphism rs1058992 is a risk of EBV-associated gastric carcinoma in Chinese population.
Acta Virol. 2018; 62(4):435-440 [PubMed] Related Publications
Microtubule-associated protein 9 (MAP9) is a mitosis-associated protein involved in bipolar spindle assembly. Following DNA damage, MAP9 stabilizes p53 via p300 and MDM2 (mouse double minute-2 homolog). The dysregulation of MAP9 was considered to be associated with tumorigenesis. Single nucleotide polymorphisms (SNPs) in key genes governing mitosis may particularly increase susceptibility to gastric carcinoma (GC). Our study demonstrated that the CC homozygous genotype of SNP rs1058992 located in the MAP9 gene was significantly correlated with EBV-associated GC (EBVaGC) in a recessive genetic model (OR = 2.558, 95% CI = 1.306-5.010, P = 0.043), and the C allele frequency of rs1058992 also showed significant correlation with EBVaGC (OR = 1.904, 95% CI = 1.141-3.179, P = 0.013). These results suggest that the MAP9 rs1058992 polymorphism is associated with risk of EBVaGC. The conversion of lysine to arginine caused by rs1058992 may affect development of EBVaGC; however, further studies in larger populations are needed to fully elucidate its role in EBVaGC. Keywords: SNP; EBV; gastric carcinoma; MAP9.

Sui Y, Han Y, Zhao X, et al.
Long non-coding RNA GClnc1 promotes tumorigenesis in osteosarcoma by inhibiting p53 signaling.
Biochem Biophys Res Commun. 2018; 507(1-4):36-42 [PubMed] Related Publications
Recent studies suggest important roles for long noncoding RNAs as essential regulators of human cancer. GClnc1 was found to be upregulated in gastric cancer, playing oncogenic roles. However, the biological function and underlying mechanism of GClnc1 in osteosarcoma (OS) remain unclear. Here, we report that GClnc1 is upregulated in OS tissues and its high expression predicts poor prognosis of patients. Functional analyses show that overexpression of GClnc1 promotes OS cells growth; whereas knockdown of GClnc1 has completely opposite effects. Consistently, overexpression of GClnc1 promotes tumorigenicity of OS cells in vivo. Mechanistically, GClnc1 directly binds to p53 and blocks the binding of p53 to acetyltransferase p300, and thereby suppresses acetylation of p53, leading to the reduced expression of p21 and BAX. This study shed light on the oncogene role of lncRNA GClnc1, a new modulator of p53 signaling, in OS.

Tian Y, Xu Y, Wang H, et al.
Comprehensive analysis of microarray expression profiles of circRNAs and lncRNAs with associated co-expression networks in human colorectal cancer.
Funct Integr Genomics. 2019; 19(2):311-327 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Increasing data demonstrate that circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) play important roles in tumorigenesis. However, the mechanisms in colorectal cancer (CRC) remain unclear. Here, hundreds of significantly expressed circRNAs, and thousands of lncRNAs as well as mRNAs were identified. By qRT-PCR, one abnormal circRNA, lncRNA, and three mRNAs were verified in 24 pairs of tissues and blood samples, respectively. Then, by GO analysis, we found that the gene expression profile of linear counterparts of upregulated circRNAs in human CRC tissues preferred positive regulation of GTPase activity, cellular protein metabolic process, and protein binding, while that of downregulated circRNAs of CRC preferred positive regulation of cellular metabolic process, acetyl-CoA metabolic process, and protein kinase C activity. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that p53 signaling pathway was an important pathway in upregulated protein-coding genes, whereas cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signaling pathway was the top enriched KEGG pathway for downregulated transcripts. Furthermore, lncRNA-mRNA co-expression analysis demonstrated that downregulated lncRNA uc001tma.3 was negatively with CDC45 and positively with ELOVL4, BVES, FLNA, and HSPB8, while upregulated lncRNA NR_110882 was positively with FZD2. In addition, lncRNA-transcription factor (TF) co-expression analysis showed that the most relevant TFs were forkhead box protein A1 (FOXA1), transcription initiation factor TFIID submint 7 (TAF7), and adenovirus early region 1A(E1A)-associated protein p300 (EP300). Our findings offer a fresh view on circRNAs and lncRNAs and provide the foundation for further study on the potential roles of circRNAs and lncRNAs in colorectal cancer.

Kim MK, Song JY, Koh DI, et al.
Reciprocal negative regulation between the tumor suppressor protein p53 and B cell CLL/lymphoma 6 (BCL6) via control of caspase-1 expression.
J Biol Chem. 2019; 294(1):299-313 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Even in the face of physiological DNA damage or expression of the tumor suppressor protein p53, B cell CLL/lymphoma 6 (BCL6) increases proliferation and antagonizes apoptotic responses in B cells. BCL6 represses

Subbaramaiah K, Iyengar NM, Morrow M, et al.
Prostaglandin E
J Biol Chem. 2019; 294(1):361-371 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Obesity increases the risk of hormone receptor-positive breast cancer in postmenopausal women. Levels of aromatase, the rate-limiting enzyme in estrogen biosynthesis, are increased in the breast tissue of obese women. Both prostaglandin E

Di Leo L, Vegliante R, Ciccarone F, et al.
Forcing ATGL expression in hepatocarcinoma cells imposes glycolytic rewiring through PPAR-α/p300-mediated acetylation of p53.
Oncogene. 2019; 38(11):1860-1875 [PubMed] Related Publications
Metabolic reprogramming is a typical feature of cancer cells aimed at sustaining high-energetic demand and proliferation rate. Here, we report clear-cut evidence for decreased expression of the adipose triglyceride lipase (ATGL), the first and rate-limiting enzyme of triglyceride hydrolysis, in both human and mouse-induced hepatocellular carcinoma (HCC). We identified metabolic rewiring as major outcome of ATGL overexpression in HCC-derived cell lines. Indeed, ATGL slackened both glucose uptake/utilization and cell proliferation in parallel with increased oxidative metabolism of fatty acids and enhanced mitochondria capacity. We ascribed these ATGL-downstream events to the activity of the tumor-suppressor p53, whose protein levels-but not transcript-were upregulated upon ATGL overexpression. The role of p53 was further assessed by abrogation of the ATGL-mediated effects upon p53 silencing or in p53-null hepatocarcinoma Hep3B cells. Furthermore, we provided insights on the molecular mechanisms governed by ATGL in HCC cells, identifying a new PPAR-α/p300 axis responsible for p53 acetylation/accumulation. Finally, we highlighted that ATGL levels confer different susceptibility of HCC cells to common therapeutic drugs, with ATGL overexpressing cells being more resistant to glycolysis inhibitors (e.g., 2-deoxyglucose and 3-bromopyruvate), compared to genotoxic compounds. Collectively, our data provide evidence for a previously uncovered tumor-suppressor function of ATGL in HCC, with the outlined molecular mechanisms shedding light on new potential targets for anticancer therapy.

Liu YS, Hsu JW, Lin HY, et al.
Bradykinin B1 receptor contributes to interleukin-8 production and glioblastoma migration through interaction of STAT3 and SP-1.
Neuropharmacology. 2019; 144:143-154 [PubMed] Related Publications
Glioblastoma (GBM), the most aggressive brain tumor, has a poor prognosis due to the ease of migration to surrounding healthy brain tissue. Recent studies have shown that bradykinin receptors are involved in the progression of various cancers. However, the molecular mechanism and pathological role of bradykinin receptors remains unclear. We observed the expressions of two major bradykinin receptors, B1R and B2R, in two different human GBM cell lines, U87 and GBM8901. Cytokine array analysis showed that bradykinin increases the production of interleukin (IL)-8 in GBM via B1R. Higher B1R levels correlate with IL-8 expression in U87 and GBM8901. We observed increased levels of phosphorylated STAT3 and SP-1 in the nucleus as well. Using chromatin immunoprecipitation assay, we found that STAT3 and SP-1 mediate IL-8 expression, which gets abrogated by the inhibition of FAK and STAT3. We further demonstrated that IL-8 expression and cell migration are also regulated by the SP-1. In addition, expression levels of STAT3 and SP-1 positively correlate with clinicopathological grades of gliomas. Interestingly, our results found that inhibition of HDAC increases IL-8 expression. Moreover, stimulation with bradykinin caused increases in acetylated SP-1 and p300 complex formation, which are abrogated by inhibition of FAK and STAT3. Meanwhile, knockdown of SP-1 and p300 decreased the augmentation of bradykinin-induced IL-8 expression. These results indicate that bradykinin-induced IL-8 expression is dependent on B1R which causes phosphorylated STAT3 and acetylated SP-1 to translocate to the nucleus, hence resulting in GBM migration.

Devan J, Janikova A, Mraz M
New concepts in follicular lymphoma biology: From BCL2 to epigenetic regulators and non-coding RNAs.
Semin Oncol. 2018; 45(5-6):291-302 [PubMed] Related Publications
The molecular pathogenesis of follicular lymphoma (FL) was partially revealed 3 decades ago, with the discovery of the translocation that brings BCL2 under the influence of immunoglobulin heavy chain enhancers in a vast majority of cases. Despite the importance of this seminal observation, it has become increasingly clear that additional genetic alterations need to occur to trigger neoplastic transformation and disease progression. The evolution of FL involves developmental arrest and disruption of the normal function of one or more of epigenetic regulators including KMT2D/MLL2, EZH2, CBP/CREBBP, p300/EP300, and HIST1H1 in >95% of cases. B-cells "arrested" in germinal centers acquire dozens of additional genetic aberrations that influence key pathways controlling their physiological development including B Cell Receptor (BCR) signaling, PI3K/AKT, TLR, mTOR, NF-κB, JAK/STAT, MAPK, CD40/CD40L, chemokine, and interleukin signaling. Additionally, most cases of FL do not result from linear accumulation of genomic aberrations, but rather evolve from a common progenitor cell population by diverse evolution, creating multiple FL subclones in one patient. Moreover, one of the subclones might acquire a combination of aberrations involving genes controlling cell survival and proliferation including MDM2, CDKN2A/B, BCL6, MYC, TP53, β2M, FOXO1, MYD88, STAT3, or miR-17-92, and this can lead to the transformation of an initially indolent FL to an aggressive lymphoma (2%-3% risk per year). The complexity of the disease is also underscored by the importance of its interactions with the microenvironment that can substantially influence disease development and prognosis. Interpreting individual aberrations in relation to their impact on normal processes, their frequency, position in the disease evolution, and the consequences of their (co)occurrence, are the basis for understanding FL pathogenesis. This is necessary for the identification of patients with risk of early progression or transformation, for the development of novel targeted therapies, and for personalized treatment approaches. In this review, we summarize recent knowledge of molecular pathways and microenvironmental components involved in FL biology, and discuss them in the context of physiological B-cell development, FL evolution, and targeted therapies.

Shao G, Liu Y, Ma T, et al.
GCN5 inhibition prevents IL-6-induced prostate cancer metastases through PI3K/PTEN/Akt signaling by inactivating Egr-1.
Biosci Rep. 2018; 38(6) [PubMed] Article available free on PMC after 04/01/2020 Related Publications
General control non-derepressible 5 (GCN5) is ectopically expressed in different types of human cancer and association with the carcinogenesis, development, and poor prognosis of cancers. The present study was aimed to investigate the potential role and related mechanisms of GCN5 in IL-6-treated prostate cancer (PCa) cell. The results showed that an elevated GCN5 expression was stimulated by IL-6. Knockdown of GCN5 significantly inhibited IL-6-driven proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). Moreover, early growth response-1 (Egr-1) expression was elevated by IL-6 treatment and GCN5 siRNA down-regulated the expression of Egr-1. Furthermore, overexpression of Egr-1 attenuated the effects of GCN5 silence on cell proliferation, migration, invasion, and EMT in PCa. Besides, knockdown of GCN5 resulted in the down-regulation of p-Akt and up-regulation of PTEN, which was partly impeded by Egr-1 overexpression. The effects of GCN5 overexpression on cell proliferation and invasion were suppressed by LY294002, In conclusion, these data demonstrated the negative effect of up-regulated GCN5 in IL-6-induced metastasis and EMT in PCa cells through PI3K/PTEN/Akt signaling pathway down-regulating Egr-1 expression.

Zhang H, Wang Y, Dou J, et al.
Acetylation of AGO2 promotes cancer progression by increasing oncogenic miR-19b biogenesis.
Oncogene. 2019; 38(9):1410-1431 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Argonaute2 (AGO2) is an effector of small RNA mediated gene silencing. Increasing evidence show that post-translational modifications of AGO2 can change miRNA activity at specific or global levels. Among the six mature miRNAs that are encoded by miR-17-92, miR-19b1 is the most powerful to exert the oncogenic properties of the entire cluster. Here we identify that AGO2 can be acetylated by P300/CBP and deacetylated by HDAC7, and that acetylation occurs at three sites K720, K493, and K355. Mutation of K493R/K720R, but not K355R at AGO2, inhibits miR-19b biogenesis. We demonstrate that acetylation of AGO2 specifically increases its recruiting pre-miR-19b1 to form the miPDC (miRNA precursor deposit complex), thereby to enhance miR-19b maturation. The motif UGUGUG in the terminal-loop of pre-miR-19b1, as a specific processing feature that is recognized and bound by acetylated AGO2, is essential for the assembly of miRISC (miRNA-induced silencing complex) loading complex. Analyses on public clinical data, xenograft mouse models, and IHC and ISH staining of lung cancer tissues, further confirm that the high levels of both AGO2 acetylation and miR-19b correlate with poor prognosis in lung cancer patients. Our finding reveals a novel function of AGO2 acetylation in increasing oncogenic miR-19b biogenesis and suggests that modulation of AGO2 acetylation has potential clinical implications.

Lu W, Xiong H, Chen Y, et al.
Discovery and biological evaluation of thiobarbituric derivatives as potent p300/CBP inhibitors.
Bioorg Med Chem. 2018; 26(20):5397-5407 [PubMed] Related Publications
Histone acetyltransferases (HATs) relieve transcriptional repression by preferentially acetylation of ε-amino group of lysine residues on histones. Dysregulation of HATs is strongly correlated with etiology of several diseases especially cancer, thus highlighting the utmost significance of the development of small molecule inhibitors against this potential therapeutic target. In the present study, through virtual screening and iterative optimization, we identified DCH36_06 as a bona fide, potent p300/CBP inhibitor. DCH36_06 mediated p300/CBP inhibition leading to hypoacetylation on H3K18 in leukemic cells. The suppression of p300/CBP activity retarded cell proliferation in several leukemic cell lines. In addition, DCH36_06 arrested cell cycle at G1 phase and induced apoptosis via activation of capase3, caspase9 and PARP that elucidated the molecular mechanism of its anti-proliferation activity. In transcriptome analysis, DCH36_06 altered downstream gene expression and apoptotic pathways-related genes verified by real-time PCR. Importantly, DCH36_06 blocked the leukemic xenograft growth in mice supporting its potential for in vivo use that underlies the therapeutic potential for p300/CBP inhibitors in clinical translation. Taken together, our findings suggest that DCH36_06 may serve as a qualified chemical tool to decode the acetylome code and open up new opportunities for clinical intervention.

Shin SH, Lee GY, Lee M, et al.
Aberrant expression of CITED2 promotes prostate cancer metastasis by activating the nucleolin-AKT pathway.
Nat Commun. 2018; 9(1):4113 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
Despite many efforts to develop hormone therapy and chemotherapy, no effective strategy to suppress prostate cancer metastasis has been established because the metastasis is not well understood. We here investigate a role of CBP/p300-interacting transactivator with E/D-rich carboxy-terminal domain-2 (CITED2) in prostate cancer metastasis. CITED2 is highly expressed in metastatic prostate cancer, and its expression is correlated with poor survival. The CITED2 gene is highly activated by ETS-related gene that is overexpressed due to chromosomal translocation. CITED2 acts as a molecular chaperone to guide PRMT5 and p300 to nucleolin, thereby activating nucleolin. Informatics and experimental data suggest that the CITED2-nucleolin axis is involved in prostate cancer metastasis. This axis stimulates cell migration through the epithelial-mesenchymal transition and promotes cancer metastasis in a xenograft mouse model. Our results suggest that CITED2 plays a metastasis-promoting role in prostate cancer and thus could be a target for preventing prostate cancer metastasis.

Jin ML, Kim YW, Jeong KW
BAF53A regulates androgen receptor-mediated gene expression and proliferation in LNCaP cells.
Biochem Biophys Res Commun. 2018; 505(2):618-623 [PubMed] Related Publications
The actin-like protein of the SWI/SNF complex, BAF53A, regulates gene expression by the gene-specific chromatin remodeling of target genes. However, the function of BAF53A in the androgen receptor pathway in prostate cancer cells remains unclear. Here, we demonstrated that BAF53A positively regulates the expression of endogenous AR target genes (e.g. PSA, TMPRSS2, FKBP5, and KLK2) in LNCaP cells. It functions as a coactivator in AR-mediated transcription by interacting with other nuclear receptor coactivators, such as p300 and FLII, and is associated with AR in the presence of dihydrotestosterone (DHT). The DHT-induced recruitment of BAF53A to the proximal and distal androgen response elements (AREs) of the PSA gene in the presence of BRG1 (but not BRM) was inhibited by an AR antagonist, suggesting the coactivator function of BAF53A in the SWI/SNF complex. Depletion of BAF53A in LNCaP cells resulted in a significant decrease in growth rate. Furthermore, the expression of BAF53A in prostate cancer tissue was significantly elevated, compared to that in normal prostate tissue, and correlated with the expression of AR, and BRG1, but not BRM. Therefore, our results suggested that BAF53A plays an important role in the expression of AR target genes in prostate cancer, and can be used clinically for the treatment of prostate cancer.

Wang YC, Wu YS, Hung CY, et al.
USP24 induces IL-6 in tumor-associated microenvironment by stabilizing p300 and β-TrCP and promotes cancer malignancy.
Nat Commun. 2018; 9(1):3996 [PubMed] Article available free on PMC after 04/01/2020 Related Publications
We have previously demonstrated that USP24 is involved in cancer progression. Here, we found that USP24 expression is upregulated in M2 macrophages and lung cancer cells. Conditioned medium from USP24-knockdown M2 macrophages decreases the migratory and chemotactic activity of lung cancer cells and the angiogenic properties of human microvascular endothelial cell 1 (HMEC-1). IL-6 expression is significantly decreased in USP24-knockdown M2 macrophages and lung cancer cells, and IL-6-replenished conditioned medium restores the migratory, chemotactic and angiogenetic properties of the cells. USP24 stabilizes p300 and β-TrCP to increase the levels of histone-3 acetylation and NF-κB, and decreases the levels of DNMT1 and IκB, thereby increasing IL-6 transcription in M2 macrophages and lung cancer cells, results in cancer malignancy finally. IL-6 has previously been a target for cancer drug development. Here, we provide direct evidence to support that USP24 promotes IL-6 expression, which might be beneficial for cancer therapy.

Xu H, Yao F
Microarray-Based Gene Expression Analysis Identifies Potential Diagnostic and Prognostic Biomarkers for Waldenström Macroglobulinemia.
Acta Haematol. 2018; 140(2):87-96 [PubMed] Related Publications
Waldenström macroglobulinemia (WM), also known as lymphoplasmacytic lymphoma, is rare but a clinicopathologically distinct B-cell malignancy. This study assessed differentially expressed genes (DEGs) to identify potential WM biomarkers and uncover the underlying the molecular mechanisms of WM progression using gene expression profiles from the Gene Expression Omnibus database. DEGs were identified using the LIMMA package and their potential functions were then analyzed by using the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses and the protein-protein interaction (PPI) network analysis by using the Search Tool for the Retrieval of Interacting Genes/Proteins database. Data showed that among 1,756 DEGs, 926 were upregulated and 830 were downregulated by comparing WM BM CD19+ with normal PB CD19+ B cell samples, whereas 241 DEGs (95 upregulated and 146 downregulated) were identified by comparing WM BM CD138+ with normal BM CD138+ plasma cell samples. The DEGs were enriched in different GO terms and pathways, including the apoptotic process, cell cycle arrest, immune response, cell adhesion, mitogen-activated protein kinase signaling pathway, toll-like receptor signaling pathway, and the gonadotropin-releasing hormone signaling pathway. Hub nodes in the PPI network included CDK1, JUN, CREBBP, EP300, CAD, CDK2, and MAPK14. Bioinformatics analysis of the GSE9656 dataset identified 7 hub genes that might play an important role in WM development and progression. Some of the candidate genes and pathways may serve as promising therapeutic targets for WM.

Huang X, Yan J, Zhang M, et al.
Targeting Epigenetic Crosstalk as a Therapeutic Strategy for EZH2-Aberrant Solid Tumors.
Cell. 2018; 175(1):186-199.e19 [PubMed] Related Publications
Mutations or aberrant upregulation of EZH2 occur frequently in human cancers, yet clinical benefits of EZH2 inhibitor (EZH2i) remain unsatisfactory and limited to certain hematological malignancies. We profile global posttranslational histone modification changes across a large panel of cancer cell lines with various sensitivities to EZH2i. We report here oncogenic transcriptional reprogramming mediated by MLL1's interaction with the p300/CBP complex, which directs H3K27me loss to reciprocal H3K27ac gain and restricts EZH2i response. Concurrent inhibition of H3K27me and H3K27ac results in transcriptional repression and MAPK pathway dependency in cancer subsets. In preclinical models encompassing a broad spectrum of EZH2-aberrant solid tumors, a combination of EZH2 and BRD4 inhibitors, or a triple-combination including MAPK inhibition display robust efficacy with very tolerable toxicity. Our results suggest an attractive precision treatment strategy for EZH2-aberrant tumors on the basis of tumor-intrinsic MLL1 expression and concurrent inhibition of epigenetic crosstalk and feedback MAPK activation.

Massillo C, Dalton GN, Porretti J, et al.
CTBP1/CYP19A1/estradiol axis together with adipose tissue impacts over prostate cancer growth associated to metabolic syndrome.
Int J Cancer. 2019; 144(5):1115-1127 [PubMed] Related Publications
Metabolic syndrome (MeS) increases prostate cancer (PCa) risk and aggressiveness. C-terminal binding protein 1 (CTBP1) is a transcriptional co-repressor of tumor suppressor genes that is activated by low NAD

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