Details of a Researcher - SUZUKI Hiromu

Misc - SUZUKI Hiromu

Division display 381 - 400 of about 424 ／ All the affair displays >>

Aberrant methylation and histone deacetylation associated with silencing of SLC5A8 in gastric cancer

M Ueno, M Toyota, K Akino, H Suzuki, M Kusano, A Satoh, H Mita, Y Sasaki, M Nojima, K Yanagihara, Y Hinoda, T Tokino, K Imai

TUMOR BIOLOGY ( KARGER ) 25 ( 3 ) 134 - 140 2004

Aberrant methylation of a sodium co-transporter, solute carrier family 5 member 8 gene (SLC5A8), has been detected in a subset of colorectal cancers, suggesting SLC5A8 may also serve as a tumor suppressor. To further investigate the role of epigenetic inactivation of SLC5A8 expression in gastric cancer, we determined the methylation status of the SLC5A8 5' CpG island (CGI) in a panel of gastric cancer cell lines and primary gastric cancers. We detected methylation of the 5' CGI in ten of twelve gastric cancer cell lines, and five of those showed dense methylation, which correlated with the absence of SLC5A8 transcription. Aberrant methylation of SLC5A8 was also detected in 23 of 71 (30%) primary gastric cancers, indicating that epigenetic inactivation of SLC5A8 is not a cell-line-specific phenomenon. SLC5A8 expression was restored in methylated cell lines by treatment with 5-aza-2'-deoxycytidine, a methyltransferase inhibitor. In addition, chromatin immunoprecipitation assays showed that acetylation of histone H3 in the 5' region of the gene correlated directly with SLC5A8 expression and inversely with DNA methylation. It thus appears that aberrant methylation of its 5' CGI and histone deacetylation play key roles in silencing SLC5A8 expression in gastric cancers. Copyright (C) 2004 S. Karger AG, Basel.

DOI

大腸癌における分泌型Frizzled関連蛋白遺伝子のエピジェネティックな不活化は大腸癌におけるWntシグナル経路活性化を補完する

鈴木拓, 豊田実, 野島正寛, 秋野公臣, 見田裕章, 佐々木泰史, 苗代康可, 時野隆至, 森満

日本癌学会総会記事 63rd 2004

J-GLOBAL

卵巣癌におけるTCF2遺伝子のエピジェネティックな異常

寺沢勝彦, 豊田実, 寒河江悟, 鈴木拓, 秋野公臣, 荻和弘, 佐々木泰史, 見田裕章, 工藤隆一

日本癌学会総会記事 63rd 2004

J-GLOBAL

造血器腫ようにおけるアポトーシス関連遺伝子のエピジェネティックな異常の解析

高橋文彦, 豊田実, 村井政史, 鈴木拓, 見田裕章, 佐々木泰史, 石田禎夫, 時野隆至, 今井浩三

日本癌学会総会記事 63rd 2004

J-GLOBAL

分裂期チェックポイント分子CHFRの制御機構の解析

見田裕章, 豊田実, 鹿島理沙, 佐藤亜由美, 荻和弘, 佐々木泰史, 鈴木拓, 苗代康可, 今井浩三

日本分子生物学会年会プログラム・講演要旨集 27th 2004

J-GLOBAL

消化器癌におけるMHC class II発現消失とClass II transactivatorのエピジェネティックな異常

佐藤亜由美, 豊田実, 池田英之, 鈴木拓, 見田裕章, 秋野公臣, 佐々木泰史, 時野隆至, 今井浩三

日本癌学会総会記事 63rd 2004

J-GLOBAL

ヒト胃癌におけるナトリウムトランスポーターファミリー遺伝子SLC5A8の異常メチル化と発現抑制

上野理子, 豊田実, 秋野公臣, 見田裕章, 村井政史, 佐々木泰史, 鈴木拓, 遠藤高夫, 時野隆至

日本癌学会総会記事 63rd 2004

J-GLOBAL

分裂期チェックポイント遺伝子CHFRの機能解析

見田裕章, 豊田実, 佐藤亜由美, 荻和弘, 佐々木泰史, 苗代康可, 秋野公臣, 鈴木拓, 今井浩三

日本癌学会総会記事 63rd 2004

J-GLOBAL

消化管癌におけるSEZ6L遺伝子のエピジェネティックな不活化

野島正寛, 鈴木拓, 豊田実, 秋野公臣, 見田裕章, 佐々木泰史, 時野隆至, 今井浩三

日本癌学会総会記事 63rd 2004

J-GLOBAL

RASシグナル伝達におけるGenetic/Epigenetic異常の解析

秋野公臣, 豊田実, 鈴木拓, 草野真暢, 苗代康可, 見田裕章, 佐々木泰史, 今井浩三, 時野隆至

日本癌学会総会記事 63rd 2004

J-GLOBAL

GATA-4 and GATA-5 transcription factor genes and potential downstream antitumor target genes are epigenetically silenced in colorectal and gastric cancer

Y Akiyama, N Watkins, H Suzuki, KW Jair, M van Engeland, M Esteller, H Sakai, CY Ren, Y Yuasa, JG Herman, SB Baylin

MOLECULAR AND CELLULAR BIOLOGY ( AMER SOC MICROBIOLOGY ) 23 ( 23 ) 8429 - 8439 2003.12

The GATA family of transcription factors participates in gastrointestinal (GI) development. Increases in GATA-4 and -5 expression occur in differentiation and GATA-6 expression in proliferation in embryonic and adult settings. We now show that in colorectal cancer (CRC) and gastric cancer promoter hypermethylation and transcriptional silencing are frequent for GATA-4 and -5 but are never seen for GATA-6. Potential antitumor target genes upregulated by GATA-4 and -5, the trefoil factors, inhibinalpha, and disabled-2 (Dab2) are also silenced, in GI cancers, with associated methylation of the promoters. Drug or genetically induced demethylation simultaneously leads to expression, in CRC cells, of all of the GATA-4, -5, and downstream genes. Expression of exogenous GATA-5 overrides methylation at the downstream promoters to activate the target genes. Selection for silencing of both upstream transcription factors and their target genes in GI cancers could indicate that epigenetic silencing of the involved genes provides a summated contribution to tumor progression.

DOI PubMed

Identification of HRK as a target of epigenetic inactivation in colorectal and gastric cancer

T Obata, M Toyota, A Satoh, Y Sasaki, K Ogi, K Akino, H Suzuki, M Murai, T Kikuchi, H Mita, F Itoh, JPJ Issa, T Tokino, K Imai

CLINICAL CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 9 ( 17 ) 6410 - 6418 2003.12

Purpose: Aberrant methylation of CpG islands can be a good molecular marker for identifying genes inactivated in cancer. We found the proapoptotic gene HRK to be a target for hypermethylation in human cancers and examined the role of such methylation in silencing the gene's expression. Experimental Design: Methylation of HRK was evaluated by bisulfite-PCR and bisulfite sequencing in a group of colorectal and gastric cancer cell lines and primary cancers. Gene expression and histone acetylation were examined by reverse transcription-PCR and chromatin immunoprecipitation analyses, respectively. Apoptosis of cancer cells after treatment with a DNA methyltransferase inhibitor and/or histone deacetylase inhibitor was examined with fluorescence-activated cell-sorting analysis. Results: The region around the HRK transcription start site was methylated in 36% of colorectal and 32% of gastric cancer cell lines and was closely associated with loss of expression in those cell types. HRK expression was restored by treatment with a methyltransferase inhibitor, 5-aza-deoxycytidine, and enhanced further by addition of histone deacetylase inhibitor trichostatin A or depsipeptide. Such restoration of HRK expression was well correlated with induction of apoptosis and enhancement of Adriamycin-induced apoptosis. Expression of other proapoptotic genes, including BAX, BAD, BID, and PUMA, was unaffected by treatment with 5-aza-deoxycytidine. Aberrant methylation of HRK was also frequently detected in primary colorectal cancers that showed methylation of multiple genes, including p16INK4A and hMLH1, and was associated with wild-type p53. Conclusion: HPK methylation can be a useful molecular target for cancer therapy in a subset of colorectal and gastric cancers.

Epigenetic inactivation of CHFR and sensitivity to microtubule inhibitors in gastric cancer

A Satoh, M Toyota, F Itoh, Y Sasaki, H Suzuki, K Ogi, T Kikuchi, H Mita, T Yamashita, T Kojima, M Kusano, M Fujita, M Hosokawa, T Endo, T Tokino, K Imai

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 63 ( 24 ) 8606 - 8613 2003.12

Mitotic checkpoints prevent errors in chromosome segregation that can lead to neoplasia. Therefore, it is notable that gastric cancers often show impaired checkpoint function. In the present study, we examined the functional consequences of epigenetic inactivation of the mitotic checkpoint gene CHFR in gastric cancers. CHFR expression was silenced by DNA methylation of the 5' region of the gene in 20% of the gastric cancer cell tines tested and in 39% of primary gastric cancers; expression could be restored by treatment with 5-aza-2'-deoxycytidine, a methyltransferase inhibitor. In addition, histones H3 and H4 were found to be deacetylated in cell lines showing aberrant methylation, indicating a role for histone deacetylation in the methylation-dependent gene silencing. Cells not expressing CHFR showed impaired checkpoint function, which led to nuclear localization of cyclin Ill after treatment with docetaxel or paclitaxel, two microtubule inhibitors. Apparently, the absence of CHFR is associated with sensitivity of cells to mitotic stress caused bit microtubule inhibition, and restoration of CHFR expression by 5-aza-2'-deoxycytidine or adenoviral gene transfer restored the checkpoint. By affecting mitotic checkpoint function, CHFR inactivation likely plays a key role in tumorigenesis in gastric cancer. Moreover, the aberrant methylation of CHFR appears to be a good molecular marker with which to predict the sensitivity of gastric cancers to microtubule inhibitors.

Berrant methylation and gene silencing of proapoptotic genes, hrk, in gastrointestinal tumors.

F Itoh, M Toyota, T Obata, A Satoh, Y Sasaki, H Suzuki, T Tokino, JPJ Issa, K Imai

CLINICAL CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 9 ( 16 ) 6160S - 6160S 2003.12

Research paper, summary (international conference)

Epigenetic inactivation of CHFR in human tumors

M Toyota, Y Sasaki, A Satoh, K Ogi, T Kikuchi, H Suzuki, H Mita, N Tanaka, F Itoh, JPJ Issa, KW Jair, KE Schuebel, K Imai, T Tokino

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA ( NATL ACAD SCIENCES ) 100 ( 13 ) 7818 - 7823 2003.06

Cell-cycle checkpoints controlling the orderly progression through mitosis are frequently disrupted in human cancers. One such checkpoint, entry into metaphase, is regulated by the CHFR gene encoding a protein possessing forkhead-associated and RING finger domains as well as ubiquitin-ligase activity. Although defects in this checkpoint have been described, the molecular basis and prevalence of CHFR inactivation in human tumors are still not fully understood. To address this question, we analyzed the pattern of CHFR expression in a number of human cancer cell lines and primary tumors. We found CpG methylation-dependent silencing of CHFR expression in 45% of cancer cell lines, 40% of primary colorectal cancers, 53% of colorectal adenomas, and 30% of primary head and neck cancers. Expression of CHFR was precisely correlated with both CpG methylation and deacetylation of histones H3 and H4 in the CpG-rich regulatory region. Moreover, CpG methylation and thus silencing of CHFR depended on the activities of two DNA methyltransferases, DNMT1 and DNMT3b, as their genetic inactivation restored CHFR expression. Finally, cells with CHFR methylation had an intrinsically high mitotic index when treated with microtubule inhibitor. This means that cells in which CHFR was epigenetically inactivated constitute loss-of-function alleles for mitotic checkpoint control. Taken together, these findings shed light on a pathway by which mitotic checkpoint is bypassed in cancer cells and suggest that inactivation of checkpoint genes is much more widespread than previously suspected.

DOI PubMed CiNii

Rapidly growing early gastric cancer with microsatellite instability

K Yamashita, N Kato, H Takahashi, H Shimizu, H Suzuki, S Motoya, Y Arimura, T Endo, H Ura, S Ichimiya, K Imai

JOURNAL OF GASTROENTEROLOGY ( SPRINGER-VERLAG TOKYO ) 38 ( 2 ) 170 - 174 2003.02

A 77-year-old man underwent gastrointestinal endoscopy that revealed a small flat elevated lesion in the gastric antrum. Endoscopically, we assessed the tumor as intramucosal cancer or adenoma, and biopsy specimens were diagnosed as showing borderline malignancy. At the second examination, performed 6 months later, the elevated lesion had grown, showing remarkable changes in its appearance, and a diagnosis of adenocarcinoma was confirmed pathologically. The patient underwent distal gastrectomy about 8 months after the first examination, and the tumor in the resected specimens showed a moderately differentiated adenocarcinoma invading through the entire submucosal layer, with metastasis to a regional lymph node. Microsatellite analysis of this early gastric cancer disclosed mutations in all six markers examined, indicating high-level microsatellite instability (NISI-H). The tumor also showed frameshift mutations of TGFbetaRII and BAX genes, as well as hypermethylation of the hMLH1 promoter. These results suggest that a deficiency of the mismatch repair system played a critical role in the progression of this cancer.

DOI PubMed

ヒト胃癌におけるナトリウムトランスポーターファミリー遺伝子SLC5A8の異常メチル化と発現抑制

田賀理子, 豊田実, 秋野公臣, 佐藤亜由美, 見田裕章, 村井政史, 佐々木泰史, 鈴木拓, 時野隆至

日本分子生物学会年会プログラム・講演要旨集 26th 2003

J-GLOBAL

口腔へん平上皮癌におけるM期チェックポイント遺伝子の発現異常とmicrotubule inhibitor感受性

荻和弘, 豊田実, 田中信幸, 野口誠, 佐藤亜由美, 佐々木泰史, 見田裕章, 鈴木拓, 今井浩三

日本癌学会総会記事 62nd 2003

J-GLOBAL

新しいユビキチンリガーゼCHFRの不活化とM期チェックポイント制御における役割

佐藤亜由美, 豊田実, 佐々木泰史, 見田裕章, 荻和弘, 鈴木拓, 遠藤高夫, 伊東文生, 時野隆至

日本癌学会総会記事 62nd 2003