Identification of coexistence of DNA methylation and H3K27me3 specifically in cancer cells as a promising target for epigenetic therapy.

Abstract:

:Alterations of epigenetic modifications are promising targets for cancer therapy, and several epigenetic drugs are now being clinically utilized. At the same time, individual epigenetic modifications have physiological functions in normal cells, and cancer cell specificity is considered difficult to achieve using a drug against a single epigenetic modification. To overcome this limitation, a combination of epigenetic modifications specifically or preferentially present in cancer cells is a candidate target. In this study, we aimed to demonstrate (i) the presence of a cancer cell-specific combination of epigenetic modifications by focusing on DNA methylation and trimethylation of histone H3 lysine 27 (H3K27me3) and (ii) the therapeutic efficacy of a combination of DNA demethylation and EZH2 inhibition. Analyses of DNA methylation and H3K27me3 in human colon, breast and prostate cancer cell lines revealed that 24.7±4.1% of DNA methylated genes had both DNA methylation and H3K27me3 (dual modification) in cancer cells, while it was 11.8±7.1% in normal cells. Combined treatment with a DNA demethylating agent, 5-aza-2'-deoxycytidine (5-aza-dC) and an EZH2 inhibitor, GSK126, induced marked re-expression of genes with the dual modification, including known tumor-suppressor genes such as IGFBP7 and SFRP1, and showed an additive inhibitory effect on growth of cancer cells in vitro. Finally, an in vivo combined treatment with 5-aza-dC and GSK126 inhibited growth of xenograft tumors more efficiently than a single treatment with 5-aza-dC. These results showed that the dual modification exists specifically in cancer cells and is a promising target for cancer cell-specific epigenetic therapy.

journal_name

Carcinogenesis

journal_title

Carcinogenesis

authors

Takeshima H,Wakabayashi M,Hattori N,Yamashita S,Ushijima T

doi

10.1093/carcin/bgu238

subject

Has Abstract

pub_date

2015-02-01 00:00:00

pages

192-201

issue

2

eissn

0143-3334

issn

1460-2180

pii

bgu238

journal_volume

36

pub_type

杂志文章
  • Formation of N-7-(2-carbamoyl-2-hydroxyethyl)guanine in DNA of the mouse and the rat following intraperitoneal administration of [14C]acrylamide.

    abstract::Acrylamide is an alkylating agent which reacts very slowly in direct reactions with DNA and is negative in the Ames test, but is carcinogenic in mice and rats. In order to explain the cancer-initiating properties of acrylamide we have studied DNA adduct formation in vitro with a metabolizing system and in vivo in mice...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/16.5.1161

    authors: Segerbäck D,Calleman CJ,Schroeder JL,Costa LG,Faustman EM

    更新日期:1995-05-01 00:00:00

  • Mouse models for ROS1-fusion-positive lung cancers and their application to the analysis of multikinase inhibitor efficiency.

    abstract::ROS1-fusion genes, resulting from chromosomal rearrangement, have been reported in 1-2% of human non-small cell lung cancer cases. More than 10 distinct ROS1-fusion genes, including break-point variants, have been identified to date. In this study, to investigate the in vivo oncogenic activities of one of the most fre...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgw028

    authors: Inoue M,Toki H,Matsui J,Togashi Y,Dobashi A,Fukumura R,Gondo Y,Minowa O,Tanaka N,Mori S,Takeuchi K,Noda T

    更新日期:2016-05-01 00:00:00

  • Measurement of adducts of benzoquinone with hemoglobin and albumin.

    abstract::Benzoquinones (BQ) are genotoxic species that stem from metabolism of phenolic compounds. We have developed a method for measuring adducts of 1,2- and 1,4-benzoquinone (1,2-BQ and 1,4-BQ) with cysteine residues of hemoglobin (Hb) and albumin (Alb). The method employs a reductive catalyst (Raney nickel) to selectively ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/14.9.1927

    authors: McDonald TA,Waidyanatha S,Rappaport SM

    更新日期:1993-09-01 00:00:00

  • Simple methods for quantifying mutagenic heterocyclic aromatic amines in food products.

    abstract::Two solid-phase extraction methods were developed for the determination of mutagenic heterocyclic aromatic amines in heated meat products. The copper phthalocyanine (CPC) tandem extraction was performed on coupled cartridges of diatomaceous earth and CPC-derivatized Sephasorb HP, followed by further clean-up on Sephas...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/11.9.1597

    authors: Gross GA

    更新日期:1990-09-01 00:00:00

  • Mutagenicity of the mononitrobenzo[a]pyrenes in Chinese hamster ovary cells mediated by rat hepatocytes or liver S9.

    abstract::Previous studies have shown that 1- and 3-nitrobenzo[a]pyrene (NBaP) were mutagenic in the Salmonella reversion assay without exogenous activation and that 1-, 3- and 6-NBaP were mutagenic in the presence of hepatocytes or liver homogenate (S9). In the present study, 1-, 3- and 6-NBaP were tested for mutagenicity in C...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/7.4.681

    authors: Hass BS,Heflich RH,Schol HM,Chou MW,Fu PP,Casciano DA

    更新日期:1986-04-01 00:00:00

  • Distribution of u.v.-induced repair events in higher-order chromatin loops in human and hamster fibroblasts.

    abstract::The repair of u.v.-induced damage in human and rodent cells was investigated at the level of DNA loops attached to the nuclear matrix. After 2 h post-u.v. incubation, DNase I digestion studies revealed a 3- to 4-fold enrichment of repair-labeled DNA at the nuclear matrix in four xeroderma pigmentosum cell strains belo...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/7.6.995

    authors: Mullenders LH,van Kesteren AC,Bussmann CJ,van Zeeland AA,Natarajan AT

    更新日期:1986-06-01 00:00:00

  • MicroRNA-423 promotes cell growth and regulates G(1)/S transition by targeting p21Cip1/Waf1 in hepatocellular carcinoma.

    abstract::MicroRNAs (miRNAs) are small non-coding RNA molecules that are often located in genomic breakpoint regions and can act as oncogenes or tumor suppressor genes in human cancer. Our previous study showed that microRNA-423 (miR-423), which localized to the frequently amplified region of chromosome 17q11, was upregulated i...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgr199

    authors: Lin J,Huang S,Wu S,Ding J,Zhao Y,Liang L,Tian Q,Zha R,Zhan R,He X

    更新日期:2011-11-01 00:00:00

  • Reaction products of styrene oxide with guanosine in aqueous media.

    abstract::Styrene oxide was reacted with guanosine in fully aqueous conditions, and the products were purified by cation exchange chromatography and h.p.l.c. The products were characterized by u.v. and mass spectra, loss of tritium from the C-8 position and dissociation properties. About 90% of the total product was identified,...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/5.5.601

    authors: Hemminki K,Hesso A

    更新日期:1984-05-01 00:00:00

  • Generation of S phase-dependent DNA double-strand breaks by Cr(VI) exposure: involvement of ATM in Cr(VI) induction of gamma-H2AX.

    abstract::Certain hexavalent chromium [Cr(VI)] compounds are implicated as occupational respiratory carcinogens. Cr(VI) induces a broad spectrum of DNA damage, but Cr(VI)-induced DNA double-strand breaks (DSBs) have not been reported. Previously we found that Cr(VI) activates the ataxia telangiectasia mutated (ATM) kinase. ATM ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgh242

    authors: Ha L,Ceryak S,Patierno SR

    更新日期:2004-11-01 00:00:00

  • Identification of two keratinocyte stem cell regulatory loci implicated in skin carcinogenesis.

    abstract::Several converging lines of evidence suggest that keratinocyte stem cells including those clonogenic in vitro, are the target cells in skin carcinogenesis. However, the mechanism of their involvement in carcinogenesis continues to be unknown. Recently, we have demonstrated that the number of keratinocyte clonogenic st...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/24.3.417

    authors: Popova NV,Teti KA,Wu KQ,Morris RJ

    更新日期:2003-03-01 00:00:00

  • Metabolism of benzo[a]pyrene in human epidermal keratinocytes in culture.

    abstract::The metabolism of benzo[a]pyrene (BP) in cultured human epidermal keratinocytes was investigated using thin layer chromatography, high pressure liquid chromatography and cell-mediated mutagenesis assay. Epidermal keratinocytes were obtained from skin of normal subjects and all experiments were performed on primary cul...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/1.7.559

    authors: Kuroki T,Nemoto N,Kitano Y

    更新日期:1980-07-01 00:00:00

  • The P110 subunit of PI3-K is a therapeutic target of acacetin in skin cancer.

    abstract::The identification of primary molecular targets of cancer-preventive phytochemicals is essential for a comprehensive understanding of their mechanism of action. In the present study, we investigated the chemopreventive effects and molecular targets of acacetin, a flavonoid found in Robinia p seudoacacia, also known as...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgt266

    authors: Jung SK,Kim JE,Lee SY,Lee MH,Byun S,Kim YA,Lim TG,Reddy K,Huang Z,Bode AM,Lee HJ,Lee KW,Dong Z

    更新日期:2014-01-01 00:00:00

  • DNA repair by MGMT, but not AAG, causes a threshold in alkylation-induced colorectal carcinogenesis.

    abstract::Epidemiological studies indicate that N-nitroso compounds (NOC) are causally linked to colorectal cancer (CRC). NOC induce DNA alkylations, including O (6)-methylguanine (O (6)-MeG) and N-methylated purines, which are repaired by O (6)-MeG-DNA methyltransferase (MGMT) and N-alkyladenine-DNA glycosylase (AAG)-initiated...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgv114

    authors: Fahrer J,Frisch J,Nagel G,Kraus A,Dörsam B,Thomas AD,Reißig S,Waisman A,Kaina B

    更新日期:2015-10-01 00:00:00

  • DNA adduct formation and unscheduled DNA synthesis in rat esophagus in vivo after treatment with N-methyl-N-nitrosourea.

    abstract::An in vivo method for assessment of DNA adduct formation and unscheduled DNA synthesis (UDS) in the esophagus of rats was devised. Small ventral incisions were made in the neck and upper abdomen regions of 6 week old F344 rats and ligation of the esophagus with thread at the two extreme ends performed to make an esoph...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/11.2.235

    authors: Qin XS,Nakatsuru Y,Kohyama K,Ishikawa T

    更新日期:1990-02-01 00:00:00

  • Multidirectional tumor-suppressive activity of AIMP2/p38 and the enhanced susceptibility of AIMP2 heterozygous mice to carcinogenesis.

    abstract::Aminoacyl-transfer ribonucleic acid (tRNA) synthetases-interacting multifunctional protein (AIMP) 2 is a factor associated with the macromolecular protein synthesis machinery consisting of nine different aminoacyl-tRNA synthetases and three non-enzymatic factors. However, it was shown to work as a multifaceted regulat...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgp170

    authors: Choi JW,Um JY,Kundu JK,Surh YJ,Kim S

    更新日期:2009-09-01 00:00:00

  • Effects on intercellular communication in human keratinocytes and liver-derived cells of polychlorinated biphenyl congeners with differing in vivo promotion activities.

    abstract::Several purified polychlorinated biphenyl (PCB) congeners with differing toxicity/tumor promotional activities in rat liver in vivo were tested for their effects on gap-junctional intercellular communication (GJIC) in cell strains and lines derived from human liver and skin. This in vitro assay is being developed to d...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/11.6.921

    authors: Swierenga SH,Yamasaki H,Piccoli C,Robertson L,Bourgon L,Marceau N,Fitzgerald DJ

    更新日期:1990-06-01 00:00:00

  • A new synthetic route to nucleotide adducts derived from N-acetylated and unacetylated 4-aminobiphenyl.

    abstract::The carcinogen N-acetoxy-N-2-acetylaminofluorene reacts with dG and dG-containing nucleotides to give good yields of the C-8 adducts, but the analogous 4-aminobiphenyl derivative does not. Replacement of the N-acetoxy group by 2,6-dichlorobenzoyloxy circumvents this difficulty. This reaction is shown to be generally a...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/9.10.1817

    authors: Underwood GR,Price MF,Shapiro R

    更新日期:1988-10-01 00:00:00

  • Ultrastructural analysis of pancreatic carcinogenesis. V. Changes in differentiation of acinar cells during chronic treatment with N-nitrosobis(2-hydroxypropyl)amine.

    abstract::An electron microscope study was carried out on changes in the pancreatic acinar tissues of male Syrian hamsters during the course of induction of pancreatic neoplasia by lifetime weekly injections of N-nitroso-bis(2-hydroxypropyl)amine (BHP). The dominant process observed was a loss of differentiation of the acinar c...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/3.5.485

    authors: Flaks B,Moore MA,Flaks A

    更新日期:1982-01-01 00:00:00

  • DNA adduct formation and removal in hepatic chromatin fractions from rats chronically fed 2-acetylaminofluorene.

    abstract::Continuous dietary administration of the hepatocarcinogen 2-acetylaminofluorene (AAF) to rats produces a gradual increase in hepatic DNA adducts until a plateau is reached after approximately 2 weeks. The rate of DNA adduct formation remains constant through 1 month of AAF feeding, while adduct removal profiles are bi...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/11.8.1343

    authors: Poirier MC,Fullerton NF,Patterson ED,Beland FA

    更新日期:1990-08-01 00:00:00

  • Tumor-initiating activity, mutagenicity, and metabolism of methylated anthracenes.

    abstract::Specific methylated derivatives of anthracene are mutagenic in S. typhimurium and have tumor-initiating activity on mouse skin. In this study, the mutagenic activities of 1-, 2-, and 9-methylanthracene, 2,9- and 9,10-dimethylanthracene, 2,9,-10-trimethylanthracene, 2,3,9,10-tetramethylanthracene, and the photo-oxide o...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/6.10.1483

    authors: La Voie EJ,Coleman DT,Rice JE,Geddie NG,Hoffmann D

    更新日期:1985-10-01 00:00:00

  • Cooperative alterations of Rb pathway regulators in mouse primary T cell lymphomas.

    abstract::Alterations in the Rb pathway have been described in many different tumors. In order to study this cell cycle regulatory mechanism in murine T cell lymphomas, we have analyzed the RNA and protein expression of the cyclin D1, cdk4 and retinoblastoma genes in primary tumor samples. We have detected overexpression of the...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/20.9.1675

    authors: Pérez de Castro IP,Malumbres M,Santos J,Pellicer A,Fernández-Piqueras J

    更新日期:1999-09-01 00:00:00

  • 4-Hydroxybutyl(butyl)nitrosamine-induced urinary bladder cancers in mice: characterization of FHIT and survivin expression and chemopreventive effects of indomethacin.

    abstract::The administration of 4-hydroxybutyl(butyl)nitrosamine (OH-BBN) to male B6D2F1 mice yielded a high incidence of large palpable urinary bladder cancers. Since prior studies demonstrated chemopreventive effects of non-steroidal anti-inflammatory drugs (NSAIDs), we further explored the efficacy of the NSAID indomethacin ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgh352

    authors: Lubet RA,Huebner K,Fong LY,Altieri DC,Steele VE,Kopelovich L,Kavanaugh C,Juliana MM,Soong SJ,Grubbs CJ

    更新日期:2005-03-01 00:00:00

  • The HSP70 family and cancer.

    abstract::The HSP70 family of heat shock proteins consists of molecular chaperones of approximately 70kDa in size that serve critical roles in protein homeostasis. These adenosine triphosphatases unfold misfolded or denatured proteins and can keep these proteins in an unfolded, folding-competent state. They also protect nascent...

    journal_title:Carcinogenesis

    pub_type: 杂志文章,评审

    doi:10.1093/carcin/bgt111

    authors: Murphy ME

    更新日期:2013-06-01 00:00:00

  • Focal and non-focal hepatic expression of placental glutathione S-transferase in carcinogen-treated rats.

    abstract::Carcinogenesis develops in stages that have been operationally defined as initiation, promotion and progression. Although morphological end points have been described for detection and quantitation of these stages, to date initiation has been assessed only in the context of clonal growth in response to certain promoti...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/15.11.2587

    authors: Dragan YP,Campbell HA,Baker K,Vaughan J,Mass M,Pitot HC

    更新日期:1994-11-01 00:00:00

  • Comparative benefits of Nab-paclitaxel over gemcitabine or polysorbate-based docetaxel in experimental pancreatic cancer.

    abstract::Gemcitabine has limited clinical benefits in pancreatic ductal adenocarcinoma. The solvent-based traditional taxanes docetaxel and paclitaxel have not shown clinical results superior to gemcitabine. Nab-paclitaxel, a water-soluble albumin-bound paclitaxel, may carry superior distribution properties into the tumor micr...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgt227

    authors: Awasthi N,Zhang C,Schwarz AM,Hinz S,Wang C,Williams NS,Schwarz MA,Schwarz RE

    更新日期:2013-10-01 00:00:00

  • Sequential and morphological analyses of aberrant crypt foci formation in mice of differing susceptibility to azoxymethane-induced colon carcinogenesis.

    abstract::Aberrant crypt foci (ACF), putative preneoplastic lesions, are early morphological changes induced by the colon carcinogen azoxymethane (AOM). Although inbred mice differ markedly in their susceptibility to AOM carcinogenesis, we have previously shown that ACF develop in both resistant and sensitive mouse strains afte...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:

    authors: Papanikolaou A,Wang QS,Papanikolaou D,Whiteley HE,Rosenberg DW

    更新日期:2000-08-01 00:00:00

  • Prevention by thioethers of the hepatotoxicity and covalent binding to macromolecules of N-hydroxy-2-acetylaminofluorene and its sulfate ester in rat liver in vivo and in vitro.

    abstract::In order to find potentially effective compounds that could prevent the covalent binding of the carcinogen N-hydroxy-2-acetylaminofluorene (N-OH-AAF) to rat liver macromolecules in vivo, the prevention of the covalent binding to RNA of the sulfate ester of the carcinogen N-OH-AAF by a series of thioethers was investig...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/8.2.275

    authors: van den Goorbergh JA,de Wit H,Tijdens RB,Mulder GJ,Meerman JH

    更新日期:1987-02-01 00:00:00

  • Expression of cytochrome P450 and microsomal epoxide hydrolase in cervical and oral epithelial cells immortalized by human papillomavirus type 16 E6/E7 genes.

    abstract::Epidemiological evidence suggests that the presence of human papillomaviruses (HPV), when combined with smoking behaviors, considerably enhances the risk of developing oral, cervical, vulvar, and/or anal carcinomas. It is well established that the cytochrome P450 (CYP), microsomal epoxide hydrolase (mEH), and other bi...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/16.6.1391

    authors: Farin FM,Bigler LG,Oda D,McDougall JK,Omiecinski CJ

    更新日期:1995-06-01 00:00:00

  • Impaired DNA double-strand break repair contributes to chemoresistance in HIF-1 alpha-deficient mouse embryonic fibroblasts.

    abstract::A mismatch between metabolic demand and oxygen delivery leads to microenvironmental changes in solid tumors. The resulting tumor hypoxia is associated with malignant progression, therapy resistance and poor prognosis. However, the molecular mechanisms underlying therapy resistance in hypoxic tumors are not fully under...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgn231

    authors: Wirthner R,Wrann S,Balamurugan K,Wenger RH,Stiehl DP

    更新日期:2008-12-01 00:00:00

  • Microsatellite instability in aberrant crypt foci from patients without concurrent colon cancer.

    abstract::Aberrant crypt foci (ACF) are microscopic surface abnormalities that are putative precursors to colorectal cancer (CRC). ACF exhibit similar histological and molecular abnormalities to adenomas and CRC and potentially represent useful biomarkers of cancer risk. Microsatellite instability (MSI) is one molecular abnorma...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgl209

    authors: Greenspan EJ,Cyr JL,Pleau DC,Levine J,Rajan TV,Rosenberg DW,Heinen CD

    更新日期:2007-04-01 00:00:00