Misc - SUZUKI Hiromu

Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours

M Murai, M Toyota, A Satoh, H Suzuki, K Akino, H Mita, Y Sasaki, T Ishida, L Shen, G Garcia-Manero, JPJ Issa, Y Hinoda, T Tokino, K Imai

BRITISH JOURNAL OF CANCER ( NATURE PUBLISHING GROUP )  92 ( 6 ) 1165 - 1172  2005.03

　View Summary

Hypoxia is a key factor contributing to the progression of human neoplasias and to the development of resistance to chemotherapy. BNIP3 is a proapoptotic member of the Bcl-2 protein family involved in hypoxia-induced cell death. We evaluated the expression and methylation status of BNIP3 gene to better understand the role of epigenetic alteration of its expression in haematopoietic tumours. Methylation of the region around the BNIP3 transcription start site was detected in four acute lymphocytic leukaemia, one multiple myeloma and one Burkitt lymphoma cell lines, and was closely associated with silencing the gene. That expression of BNIP3 was restored by treatment with 5-aza2 '-deoxycytidine (5-aza-dC), a methyltransferase inhibitor, which confirmed the gene to be epigenetically inactivated by methylation. Notably, re-expression of BNIP3 using 5-aza2-dC also restored hypoxia-mediated cell death in methylated cell lines. Acetylation of histone H3 in the 5 ' region of the gene, which was assessed using chromatin immunoprecipitation assays, correlated directly with gene expression and inversely with DNA methylation. Among primary tumours, methylation of BNIP3 was detected in five of 34 (15%) acute lymphocytic leukaemias, six of 35 (17%) acute myelogenous leukaemias and three of 14 (21%) multiple myelomas. These results suggest that aberrant DNA methylation of the 5 ' CpG island and histone deacetylation play key roles in silencing BNIP3 expression in haematopoietic tumours.

DOI

胃癌においてメチル化により不活化している新規癌抑制遺伝子の同定

上野理子, 豊田実, 豊田実, 鈴木拓, 鈴木拓, 秋野公臣, 秋野公臣, 見田裕章, 見田裕章, 佐々木泰史, 佐々木泰史, 篠村恭久, 時野隆至, 今井浩三

日本癌学会学術総会記事   64th  2005

J-GLOBAL

分裂期チェックポイント分子CHFRの機能解析

鹿島理沙, 見田裕章, 豊田実, 豊田実, 豊田実, 佐々木泰史, 井戸川雅史, 井戸川雅史, 鈴木拓, 秋野公臣, 秋野公臣, 時野隆至

日本分子生物学会年会講演要旨集   28th  2005

J-GLOBAL

口腔へん平上皮癌における分泌型Frizzled関連蛋白遺伝子のエピジェネティックな不活化

曽我部陽平, 曽我部陽平, 鈴木拓, 鈴木拓, 鈴木拓, 豊田実, 豊田実, 豊田実, 秋野公臣, 秋野公臣, 佐々木泰史, 見田裕章, 草野真暢, 草野真暢, 今井崇, 時野隆至, 平塚博義

日本癌学会学術総会記事   64th  2005

J-GLOBAL

RASシグナル伝達におけるRASSF2遺伝子の機能解析

高橋文彦, 豊田実, 豊田実, 秋野公臣, 秋野公臣, 鈴木拓, 鈴木拓, 見田裕章, 佐々木泰史, 篠村恭久, 今井浩三, 時野隆至

日本癌学会学術総会記事   64th  2005

J-GLOBAL

分裂期チェックポイントCHFRの機能解析

鹿島理沙, 見田裕章, 豊田実, 豊田実, 豊田実, 佐々木泰史, 鈴木拓, 鈴木拓, 秋野公臣, 秋野公臣, 時野隆至

日本癌学会学術総会記事   64th  2005

J-GLOBAL

CpG Island Methylator Phenotype胃癌の分子生物・臨床病理学的特徴とEBウイルス関連胃癌との関係

草野真暢, 草野真暢, 豊田実, 豊田実, 鈴木拓, 鈴木拓, 秋野公臣, 秋野公臣, 見田裕章, 佐々木泰史, 垣内英樹, 伊東文生, 篠村恭久, 今井浩三, 時野隆至

日本癌学会学術総会記事   64th  2005

J-GLOBAL

胃癌におけるメチル化標的新規癌関連遺伝子の検討

渡辺嘉行, 渡辺嘉行, 豊田実, 豊田実, 秋野公臣, 秋野公臣, 鈴木拓, 鈴木拓, 井戸川雅史, 井戸川雅史, 鹿島里沙, 見田裕章, 佐々木泰史, 伊東文生, 時野隆至

日本分子生物学会年会講演要旨集   28th  2005

J-GLOBAL

胃癌において異常メチル化により不活化している新規遺伝子ACMG1

佐藤裕信, 豊田実, 豊田実, 鈴木拓, 鈴木拓, 秋野公臣, 秋野公臣, 見田裕章, 佐々木泰史, 上野理子, 篠村恭久, 篠村恭久, 時野隆至, 今井浩三

日本癌学会学術総会記事   64th  2005

J-GLOBAL

p53によるVDR(vitamin D receptor)の発現誘導

丸山玲緒, 豊田実, 豊田実, 明石浩史, 明石浩史, 佐々木泰史, 青木文夫, 見田裕章, 鈴木拓, 鈴木拓, 篠村恭久, 今井浩三, 時野隆至

日本癌学会学術総会記事   64th  2005

J-GLOBAL

塩基配列情報を基盤とした定量的ゲノム解析法の開発と癌研究への応用

見田裕章, 豊田実, 豊田実, 丸山玲緒, 青木文夫, 明石浩史, 佐々木泰史, 鹿島理沙, 秋野公臣, 鈴木拓, 苗代康司, 井戸川雅史, 大西浩文, 大西浩文, 辰巳治之, 今井浩三, 篠村恭久, 時野隆至

日本分子生物学会年会講演要旨集   28th  2005

J-GLOBAL

5-aza-2’-deoxycytidineによるBNIP3遺伝子の発現回復はすい癌細胞における低酸素誘導性細胞死感受性を増強する

阿部環, 豊田実, 豊田実, 鈴木拓, 鈴木拓, 秋野公臣, 秋野公臣, 見田裕章, 見田裕章, 佐々木泰史, 佐々木泰史, 遠藤高夫, 篠村恭久, 時野隆至, 今井浩三

日本癌学会学術総会記事   64th  2005

J-GLOBAL

p53によるビタミンD受容体の発現誘導と抗腫よう効果の増強作用

丸山玲緒, 豊田実, 豊田実, 佐々木泰史, 青木文夫, 明石浩史, 明石浩史, 見田裕章, 鈴木拓, 鈴木拓, 今井浩三, 篠村恭久, 時野隆至

日本分子生物学会年会講演要旨集   28th  2005

J-GLOBAL

SFRP, a family of new colorectal tumor suppressor candidate genes

Hiromu Suzuki, Minoru Toyota, Masanori Nojima, Mitsuru Mori, Kohzoh Imai

Nippon rinsho. Japanese journal of clinical medicine   63 ( 4 ) 707 - 719  2005

Book review, literature introduction, etc.  

　View Summary

Aberrant Wnt pathway signaling is an early progression event in up to 90% of colorectal cancers (CRC). It occurs mainly through mutations of APC or beta-catenin. We have identified frequent promoter hypermethylation and gene silencing of the secreted frizzled-related protein (SFRP) genes in CRC. SFRPs possess a domain similar to one in the Wnt receptor Frizzled proteins and can inhibit Wnt receptor binding to downregulate pathway signaling in development. We next found that restoration of SFRP function in CRC cells attenuates Wnt signaling even in the presence of downstream mutations. We also show that the epigenetic loss of SFRP function occurs early in CRC progression and may, thus, provide constitutive Wnt signaling which is required to complement downstream mutations in the evolution of CRC.

PubMed

Epigenetic inactivation of class II transactivator (CIITA) is associated with the absence of interferon-gamma-induced HLA-DR expression in colorectal and gastric cancer cells

A Satoh, M Toyota, H Ikeda, Y Morimoto, K Akino, H Mita, H Suzuki, Y Sasaki, T Kanaseki, Y Takamura, H Soejima, T Urano, K Yanagihara, T Endo, Y Hinoda, M Fujita, M Hosokawa, N Sato, T Tokino, K Imai

ONCOGENE ( NATURE PUBLISHING GROUP )  23 ( 55 ) 8876 - 8886  2004.11

　View Summary

Tightly regulated at the level of transcription, expression of MHC class II molecules varies significantly among gastrointestinal cancers. High levels of MHC class II expression are often associated with a better prognosis, which is indicative of the involvement of CD4(+) lymphocytes in tumor suppression, but the molecular mechanism by which MHC class II expression is regulated remains unclear. In the present study, we investigated the expression of one inducible MHC class II molecule, HLA-DR, and its coactivators in a panel of colorectal and gastric cancer cell lines. Interferon-gamma induced expression of HLA-DR in 14 of 20 cell lines tested; the remaining six cell lines did not express HLA-DR. Analysis of the expression of transcription factors and coactivators associated with HLA-DR revealed that the loss of CIITA expression was closely associated with the absence of HLA-DR induction. Moreover, DNA methylation of the 50 CpG island of CIITA-PIV was detected in all cancer cells that lacked CIITA. The methylation and resultant silencing of CIITA-PIV depended on the activities of two DNA methyltransferases, DNMT1 and DNMT3B, and their genetic inactivation restored CIITA-PIV expression. It thus appears that CIITA methylation is a key mechanism that enables some gastrointestinal cancer cells to escape immune surveillance.

DOI

Mammalian DNA methyltransferase 1 - Inspiration for new directions

AH Ting, KW Jair, H Suzuki, RWC Yen, SB Baylin, KE Schuebel

CELL CYCLE ( TAYLOR & FRANCIS INC )  3 ( 8 ) 1024 - 1026  2004.08

　View Summary

The role of DNA methyltransferase 1, DNMT1, in human cancer cells has recently been contested. In this setting, DNMT1's function as the sole maintenance methyltransferase was based on the assumption that its biological activity is identical to the mouse homologue. However, the application of recent technological advances, including gene targeting and siRNA mediated ablation studies, has cast doubt on this presumed role. Here, we attempt to shed light on these new data within the context of previous experiments.

CpG island hypermethylation is maintained in human colorectal cancer cells after RNAi-mediated depletion of DNMT1

AH Ting, KW Jair, H Suzuki, RWC Yen, SB Baylin, KE Schuebel

NATURE GENETICS ( NATURE PUBLISHING GROUP )  36 ( 6 ) 582 - 584  2004.06

　View Summary

The role of the primary mammalian DNA methyltransferase, DNMT1, in maintaining CpG island methylation in human colon cancer cells has recently been questioned. This controversy has arisen from discrepancies between genetic knockout and RNA interference-mediated knockdown studies. Here, we re-examined the RNA interference-based approach and found that hypermethylation of single-copy genes is maintained in cells transiently and stably depleted of DNMT1.

DOI PubMed CiNii

Deletions of chromosome 8p and loss of sFRP1 expression are progression markers of papillary bladder cancer

R Stoehr, C Wissmann, H Suzuki, R Knuechel, RC Krieg, E Klopocki, E Dahl, P Wild, H Blaszyk, G Sauter, R Simon, R Schmitt, D Zaak, F Hofstaedter, A Rosenthal, SB Baylin, C Pilarsky, A Hartmann

LABORATORY INVESTIGATION ( NATURE PUBLISHING GROUP )  84 ( 4 ) 465 - 478  2004.04

　View Summary

Many molecular alterations are known to occur in urothelial carcinoma of the bladder, but their significance for tumor progression is poorly understood. Deletions of chromosome 8p are frequently found in several tumor types and are often associated with progressive disease. In all, 99 bladder tumors were screened for deletions at 8p using loss of heterozygosity (LOH) and multicolor fluorescence in situ hybridization FISH analyses. Allelic loss on chromosome 8p in at least one marker was found in 25/99 (25%) tumors. There was a significant correlation of 8p deletions with invasive tumor growth and a highly significant association with papillary growth pattern in patients with invasive disease. cDNA array analyses revealed that secreted Frizzled-related protein 1 (sFRP1), an antagonist of Frizzled receptors and Wnt pathway activation on chromosome 8p12-11.1, is frequently downregulated in bladder cancer. To investigate sFRP1 as a candidate for a putative progression-related gene on 8p, urothelial cell lines and primary urothelial carcinomas were screened for sFRP1 expression using quantitative real-time PCR, Northern blot, immunofluorescence and immunohistochemistry (IHC). Of the investigated bladder cancers, 38% showed loss of sFRP1 expression by quantitative RT-PCR. Evaluation of the protein expression by IHC using tissue microarrays containing 776 bladder cancers revealed loss or strong reduction of sFRP1 expression in 66% of cases. SFRP1 loss was associated with higher tumor stage and grade and shorter overall survival. In addition, loss of sFRP1 was an independent indicator of poor survival in patients with papillary but not with muscle invasive bladder cancer. There were neither mutations in the coding region of sFRP1 nor homozygous deletions at 8p12-11.21. However, promoter methylation was detected using methylation-specific PCR in 29% of cases. In conclusion, we could show a close correlation of chromosome 8p deletions and progression of papillary bladder tumors. The sFRP1 gene on chromosome 8p12-11.1 could be a candidate gene for the predicted, progression-related tumor suppressor gene in bladder cancer and could contribute to urothelial carcinogenesis.

DOI

Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer

H Suzuki, DN Watkins, KW Jair, KE Schuebel, SD Markowitz, WD Chen, TP Pretlow, Bin Yang,, Y Akiyama, M van Engeland, M Toyota, T Tokino, Y Hinoda, K Imai, JG Herman, SB Baylin

NATURE GENETICS ( NATURE PUBLISHING GROUP )  36 ( 4 ) 417 - 422  2004.04

　View Summary

Aberrant WNT pathway signaling is an early progression event in 90% of colorectal cancers(1). It occurs through mutations mainly of APC and less often of CTNNB1 (encoding beta-catenin)(1-3) or AXIN2 (encoding axin-2, also known as conductin)(4). These mutations allow ligand-independent WNT signaling that culminates in abnormal accumulation of free beta-catenin in the nucleus(1-3). We previously identified frequent promoter hypermethylation and gene silencing of the genes encoding secreted frizzled-related proteins (SFRPs) in colorectal cancer(5). SFRPs possess a domain similar to one in the WNT-receptor frizzled proteins and can inhibit WNT receptor binding to downregulate pathway signaling during development(6-10). Here we show that restoration of SFRP function in colorectal cancer cells attenuates WNT signaling even in the presence of downstream mutations. We also show that the epigenetic loss of SFRP function occurs early in colorectal cancer progression and may thus provide constitutive WNT signaling that is required to complement downstream mutations in the evolution of colorectal cancer.

DOI PubMed CiNii

Inactivation of class II transactivator by DNA methylation and histone deacetylation associated with absence of HLA-DR induction by interferon-gamma in haematopoietic tumour cells

Y Morimoto, M Toyota, A Satoh, M Murai, H Mita, H Suzuki, Y Takamura, H Ikeda, T Ishida, N Sato, T Tokino, K Imai

BRITISH JOURNAL OF CANCER ( NATURE PUBLISHING GROUP )  90 ( 4 ) 844 - 852  2004.02

　View Summary

By presenting immunogenic peptides at the cell surface, major histocompatibility complex (MHC) class II molecules play a key role in the control of adaptive immune responses. Whether expressed constitutively or induced by interferon-gamma, expression of MHC class II molecules is regulated via coactivator class II transactivator (CIITA); moreover, suppression of their expression is one mechanism by which cancer cells escape host immunity. In this study, we surveyed the relationship between the expression of one MHC class II antigen, HLA-DR, and its coactivators in a group of haematopoietic cell lines, and explored the role of the aberrant DNA methylation in silencing HLA-DR expression. Among 26 cell lines studied, HLA-DR expression was lost from eight T-cell and two myeloid leukaemia cell lines, and this loss was closely associated with suppression of CIITA-PIV expression. Notably, nine of the 10 cell lines that lost CIITA-PIV expression showed methylation of the gene's 5' CpG island. Thus, DNA methylation is believed to inhibit the expression of MHC class II molecules in haematopoietic tumour cells by silencing its coactivator, CIITA-PIV. Furthermore, methylation of CIITA-PIV was detected in seven of 32 primary acute myeloid leukaemia specimens, indicating that epigenetic alteration is not a cell line-specific phenomenon. Collectively, these data suggest that, by suppressing expression of MHC class II molecules, epigenetic inactivation of CIITA provides a survival advantage to a subset of haematopoietic tumours.

DOI