Papers - SUZUKI Hiromu

Frequent epigenetic inactivation of SFRP genes in hepatocellular carcinoma

Hideyasu Takagi, Shigeru Sasaki, Hiromu Suzuki, Minoru Toyota, Reo Maruyama, Masanori Nojima, Hiroyuki Yamamoto, Masao Omata, Takashi Tokino, Kohzoh Imai, Yasuhisa Shinomura

JOURNAL OF GASTROENTEROLOGY ( SPRINGER TOKYO )  43 ( 5 ) 378 - 389  2008  [Refereed]

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Background. Activation of the Wnt signaling pathway is frequently observed in hepatocellular carcinoma (HCC), though mutation of three of its components, CTNNB1, AXIN1, and AXIN2, is observed substantially less often. Methods. We examined the relationship between Wnt signaling and epigenetic alteration of secreted frizzled-related protein (SFRP) genes in HCC. Results. We frequently detected the active form of beta-catenin and accumulation of nuclear beta-catenin in liver cancer cell lines. We detected methylation of SFRP family genes in liver cancer cell lines (SFRP1, 9/12, 75%; SFRP2, 7/12, 58%; SFRP4, 3/12, 25%; SFRP5, 7/12, 58%) and primary HCCs (SFRP1, 9/19, 47%; SFRP2, 12/19, 63%; SFRP5, 8/19, 42 %), though methylation of SFRP4 was not found in primary HCCs. SFRP methylation also was detected in hepatitis B or C virus-associated chronic hepatitis (SFRP1, 6/37, 16%; SFRP2, 14/37, 38%; SFRP5, 5/37, 14%) and liver cirrhosis (SFRP1, 10/28,36%; SFRP2,9128,32%; SFRP5, 3/28, 11%), suggesting that methylation of these genes is an early event in liver carcinogenesis. Ectopic expression of SFRPs downregulated T-cell factor/lymphocyte enhancer factor (TCF/LEF) transcriptional activity in liver cancer cells, while overexpression of a P-catenin mutant and depletion of SFRP1 using siRNA synergistically upregulated TCF/LEF transcriptional activity. Conclusions. Our results confirm the frequent methylation and silencing of Wnt antagonist genes in HCC, and suggest that their loss of function contributes to activation of Wnt signaling during hepatocarcinogenesis.

DOI PubMed

【消化器疾患とエピジェネティクス】 大腸癌でのDNAメチル化異常

野島正寛, 豊田実, 鈴木拓, 森満, 篠村恭久

分子消化器病   5   364 - 369  2008  [Refereed]

Genomic Mapping of 12p Amplifications in Gastric Cancer Reveal a 0.5-Mb Target Region Including KRAS Locus

Mita Hiroaki, Aoki Fumio, Akashi Hirofumi, Maruyama Reo, Sasaki Yasushi, Suzuki Hiromu, Idogawa Masashi, Kashima Lisa, Toyota Minoru, Imai Kohzoh, Shinomura Yasuhisa, Tokino Takashi

Tumor Biology   29   83  2008  [Refereed]

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

Suzuki H, Toyota M, Carraway H, Gabrielson E, Ohmura T, Fujikane T, Nishikawa N, Sogabe Y, Nojima M, Sonoda T, Mori M, Hirata K, Imai K, Shinomura Y, Baylin SB, Tokino T

Br J Cancer   98   1147 - 1156  2008  [Refereed]

DOI

Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors

Suzuki Hiromu, Toyota Minoru, Sato Hironobu, Nojima Masanori, Imai Kohzoh, Shinomura Yasuhisa

Japan Journal of Molecular Tumor Marker Research ( Japanese Society for Molecular Tumor Marker Research )  23   37 - 38  2008

DOI CiNii

Frequent epigenetic inactivation of DICKKOPF family genes in human gastrointestinal tumors

Hironobu Sato, Hiromu Suzuki, Minoru Toyota, Masanori Nojima, Reo Maruyama, Shigeru Sasaki, Hideyasu Takagi, Yohei Sogabe, Yasushi Sasaki, Masashi Idogawa, Tomoko Sonoda, Mitsuru Mori, Kohzoh Imai, Takashi Tokino, Yasuhisa Shinomura

CARCINOGENESIS ( OXFORD UNIV PRESS )  28 ( 12 ) 2459 - 2466  2007.12  [Refereed]

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Activation of Wnt signaling has been implicated in tumorigenesis, and epigenetic silencing of Wnt antagonist genes has been detected in various cancers. In the present study, we examined the expression and methylation of DICKKOPF (DKK) family genes in gastrointestinal cancer cell lines. We found that all known DKK genes were frequently silenced in colorectal cancer (CRC) cells (DKK1, 3/9, 33%; DKK2, 8/9, 89%; DKK3, 5/9, 56% and DKK4, 5/9, 56%), but not in normal colon mucosa. DKK1, -2 and -3 have 5' CpG islands, and show an inverse relation between expression and methylation. DKK methylation also was frequently observed in gastric cancer (GC) cell lines (DKK1, 6/16, 38%; DKK2, 15/16, 94% and DKK3, 10/16, 63%), but was seen less frequently in hepatocellular carcinoma and pancreatic cancer cell lines. DKKs also were frequently methylated in primary CRCs (DKK1, 7/58, 12%; DKK2, 45/58, 78% and DKK3, 12/58, 21%) and GCs (DKK1, 15/31, 48%; DKK2, 26/31, 84% and DKK3, 12/31, 39%). Against a background of CTNNB1 or APC mutations, Dickkopfs (Dkks) were less effective inhibitors of Wnt signaling than secreted frizzled-related proteins, though over-expression of Dkks suppressed colony formation of CRC cells with such mutations. Our results demonstrate that DKKs are frequent targets of epigenetic silencing in gastrointestinal tumors, and that loss of DKKs may facilitate tumorigenesis through beta-catenin/T-cell factor-independent mechanisms.

DOI PubMed

Gene amplification and overexpression of PRDM14 in breast cancers

Noriko Nishikawa, Minoru Toyota, Hiromu Suzuki, Toshio Honma, Tomoko Fujikane, Tousei Ohmura, Toshihiko Nishidate, Mutsmui Ohe-Toyota, Reo Maruyama, Tomoko Sonoda, Yasushi Sasaki, Takeshi Urano, Kohzoh Imai, Koichi Hirata, Takashi Tokino

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH )  67 ( 20 ) 9649 - 9657  2007.10  [Refereed]

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Several genes that encode PR (PRDI-BF1 and RIZ) domain proteins (PRDM) have been linked to human cancers. To explore the role of the PR domain family genes in breast carcinogenesis, we examined the expression profiles of 16 members of the PRDM gene family in a panel of breast cancer cell lines and primary breast cancer specimens using semiquantitative real-time PCR. We found that PRDM14 mRNA is overexpressed in about two thirds of breast cancers; moreover, immunohistochemical analysis showed that expression of PRDM14 protein is also up-regulated. Analysis of the gene copy number revealed that PRDM14 is a target of gene amplification on chromosome 8q13, which is a region where gene amplification has frequently been detected in various human tumors. Introduction of PRDM14 into cancer cells enhanced cell growth and reduced their sensitivity to chemotherapeutic drugs. Conversely, knockdown of PRDM14 by siRNA induced apoptosis in breast cancer cells and increased their sensitivity to chemotherapeutic drugs, suggesting that up-regulated expression of PRDM14 may play an important role in the proliferation of breast cancer cells. That little or no expression of PRDM14 is seen in noncancerous tissues suggests that PRDM14 could be an ideal therapeutic target for the treatment of breast cancer.

DOI PubMed

Epigenetic silencing of CDX2 is a feature of squamous esophageal cancer

MingZhou Guo, Michael G. House, Hiromu Suzuki, Ying Ye, Malcolm V. Brock, Fengmin Lu, Zhihua Liu, Anil K. Rustgi, James G. Herman

INTERNATIONAL JOURNAL OF CANCER ( WILEY-LISS )  121 ( 6 ) 1219 - 1226  2007.09  [Refereed]

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CDX2, a mammalian homologue of the homeobox gene 'caudal,' is expressed in gut epithelia and plays an important role in establishing the intestinal phenotype during development. Mice heterozygously disrupted for CDX2 develop disorganized polypoid hamartomas with glandular epithelium and stratified squamous metaplasia resembling foregut mucosa. Since no genetic disruptions of CDX2 have been reported to explain loss of gene function, we examined whether epigenetic mechanisms altered CDX2 expression. Eleven of 17 squamous esophageal cancer cell lines lacked expression of CDX2 that was restored following treatment with 5-aza-2'-deoxycytidine, while all colorectal cancer cell lines expressed CDX2. Loss of expression was associated with DNA methylation in the 5' region of CDX2 determined by methylation specific PCR and bisulfite sequencing. Methylation of CDX2 was rare in primary colorectal (I of 44 tumors, 2%) and esophageal adenocarcinoma neoplasms (2 of 43 tumors, 5%), but was common in esophageal squamous carcinoma (24 of 45 tumors, 49%). No CDX2 methylation was found in normal tissues. Using semi-quantitative RT-PCR, expression of CDX2 was found in low level in normal esophagus, at higher levels in primary adenocarcinoma of the esophagus, but not in primary squamous cancers of the esophagus. Restoration of CDX2 in silenced cell lines resulted in expression of the CDX2 target gene MUC2, a gene important in glandular differentiation. Our results suggest that the inactivation of l in esophageal cancer associated with DNA methylation may be an important determinant of the squamous or non-adenomatous phenotype. (c) 2007 Wiley-Liss, Inc.

DOI PubMed

Comparing the DNA hypermethylome with gene mutations in human colorectal cancer

Kornel E. Schuebel, Wei Chen, Leslie Cope, Sabine C. Glöckner, Hiromu Suzuki, Joo-Mi Yi, Timothy A. Chan, Leander Van Neste, Wim Van Criekinge, Sandra Van Den Bosch, Manon Van Engeland, Angela H. Ting, Kamwing Jair, Wayne Yu, Minoru Toyota, Kohzoh Imai, Nita Ahuja, James G. Herman, Stephen B. Baylin

PLoS Genetics   3 ( 9 ) 1709 - 1723  2007.09  [Refereed]

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We have developed a transcriptome-wide approach to identify genes affected by promoter CpG island DNA hypermethylation and transcriptional silencing in colorectal cancer. By screening cell lines and validating tumorspecific hypermethylation in a panel of primary human colorectal cancer samples, we estimate that nearly 5% or more of all known genes may be promoter methylated in an individual tumor. When directly compared to gene mutations, we find larger numbers of genes hypermethylated in individual tumors, and a higher frequency of hypermethylation within individual genes harboring either genetic or epigenetic changes. Thus, to enumerate the full spectrum of alterations in the human cancer genome, and to facilitate the most efficacious grouping of tumors to identify cancer biomarkers and tailor therapeutic approaches, both genetic and epigenetic screens should be undertaken. © 2007 Schuebel et al.

DOI PubMed

Comparing the DNA hypermethylome with gene mutations in human colorectal cancer

Kornel E. Schuebel, Wei Chen, Leslie Cope, Sabine C. Gloeckner, Hiromu Suzuki, Joo-Mi Yi, Timothy A. Chan, Leander Van Neste, Wim Van Criekinge, Sandra van den Bosch, Manon van Engeland, Angela H. Ting, Kamwing Jair, Wayne Yu, Minoru Toyota, Kohzoh Imai, Nita Ahuja, James G. Herman, Stephen B. Baylin

PLOS GENETICS ( PUBLIC LIBRARY SCIENCE )  3 ( 9 ) 1709 - 1723  2007.09  [Refereed]

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We have developed a transcriptome-wide approach to identify genes affected by promoter CpG island DNA hypermethylation and transcriptional silencing in colorectal cancer. By screening cell lines and validating tumor-specific hypermethylation in a panel of primary human colorectal cancer samples, we estimate that nearly 5% or more of all known genes may be promoter methylated in an individual tumor. When directly compared to gene mutations, we find larger numbers of genes hypermethylated in individual tumors, and a higher frequency of hypermethylation within individual genes harboring either genetic or epigenetic changes. Thus, to enumerate the full spectrum of alterations in the human cancer genome, and to facilitate the most efficacious grouping of tumors to identify cancer biomarkers and tailor therapeutic approaches, both genetic and epigenetic screens should be undertaken.

DOI

PRDM5 identified as a target of epigenetic silencing in colorectal and gastric cancer

Yoshiyuki Watanabe, Minoru Toyota, Yutaka Kondo, Hiromu Suzuki, Takashi Imai, Mutsumi Ohe-Toyota, Reo Maruyama, Masanori Nojima, Yasushi Sasaki, Yoshitaka Sekido, Hiroyoshi Hiratsuka, Yasuhisa Shinomura, Kohzoh Imai, Fumio Itoh, Takashi Tokino

CLINICAL CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH )  13 ( 16 ) 4786 - 4794  2007.08  [Refereed]

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Purpose: PR (PRDI-BF1 and RIZ) domain proteins (PRDM) are a subfamily of the kruppel-like zinc finger gene products that play key roles during cell differentiation and malignant transformation. The aim of the present study was to begin to examine the involvement of epigenetic alteration of PRDM expression in gastric and colorectal cancer. Experimental Design: We used real-time PCR to assess expression of PRDM1-17. In addition, we used bisulfite PCR to assess DNA methylation and chromatin immunoprecipitation to assess histone modification in colorectal and gastric cancer cell lines lacking PRDM5 expression. Results: Among the 17 PRDM family genes tested, we found that PRDM5 is the most frequently silenced in colorectal and gastric cancer cell lines. Silencing of PRDM5 was mediated by either DNA methylation or trimethylation of Lys(27) of histone H3. Introduction of PRDM5 into cancer cells suppressed cell growth, suggesting that it acts as a tumor suppressor in gastrointestinal cancers. Methylation of PRDM5 was detected in 6.6% (4 of 61) of primary colorectal and 50.0% (39 of 78) of primary gastric cancers but not in noncancerous tissue samples collected from areas adjacent to the tumors. Conclusions: Our data suggest that epigenetic alteration of PRDM5 (e.g., methylation of its 5'-CpG island or trimethylation of Lys(27) of histone H3) likely plays a key role in the progression of gastrointestinal cancers and may be a useful molecular marker.

DOI PubMed

口腔癌におけるRAS関連遺伝子の異常について(Alterations of RAS signaling pathway in oral squamous cell carcinoma)

今井 崇, 秋野 公臣, 豊田 実, 鈴木 拓, 佐々木 泰史, 見田 裕章, 井戸川 雅史, 鹿島 理沙, 曽我部 陽平, 渡邊 嘉行, 今井 浩三, 平塚 博義, 時野 隆至

日本癌学会総会記事 ( (一社)日本癌学会 )  66回   314 - 314  2007.08

デジタルゲノムスキャンにより同定された胃癌におけるK-rasゲノム増幅(Genomic amplification of K-ras in gastric cancer identified by digital genome scanning)

見田 裕章, 豊田 実, 青木 文夫, 明石 浩史, 丸山 玲緒, 佐々木 泰史, 鈴木 拓, 井戸川 雅史, 鹿島 理沙, 今井 浩三, 篠村 恭久, 時野 隆至

日本癌学会総会記事 ( (一社)日本癌学会 )  66回   231 - 231  2007.08

アデノウイルス介在性p53ファミリー遺伝子療法効果のヒストンデアセチラーゼ阻害剤FK228による増大(The Histone Deacetylase Inhibitor FK228 Increases the Efficacy of Adenovirus-mediated p53 Family Gene Therapy)

佐々木 泰史, 根岸 秀明, 井戸川 雅史, 鈴木 拓, 見田 裕章, 豊田 実, 丸山 玲緒, 明石 浩史, 篠村 恭久, 今井 浩三, 時野 隆至

日本癌学会総会記事 ( (一社)日本癌学会 )  66回   129 - 129  2007.08

CHFR有糸分裂チェックポイントタンパク質はNFκBの転写活性を抑制する(CHFR mitotic checkpoint protein inhibits the transcriptional activity of NF-κB)

鹿島 理沙, 見田 裕章, 豊田 実, 佐々木 泰史, 鈴木 拓, 井戸川 雅史, 時野 隆至

日本癌学会総会記事 ( (一社)日本癌学会 )  66回   482 - 482  2007.08

多発性骨髄腫においてDNAメチル化により不活化される遺伝子の網羅的解析(Genomic Screening for Genes Silenced by DNA Methylation in Multiple Myeloma)

丸山 玲緒, 豊田 実, 鈴木 拓, 安井 寛, 林 敏昭, 酒井 基, 石田 禎夫, 今井 浩三, 時野 隆至, 篠村 恭久

日本癌学会総会記事 ( (一社)日本癌学会 )  66回   458 - 458  2007.08

Identification of DFNA5 as a target of epigenetic inactivation in gastric cancer

Kimishige Akino, Minoru Toyota, Hiromu Suzuki, Takashi Imai, Reo Maruyama, Masanobu Kusano, Noriko Nishikawa, Yoshiyuki Watanabe, Yasushi Sasaki, Tamaki Abe, Eiichiro Yamamoto, Isao Tarasawa, Tomoko Sonoda, Mitsuru Mori, Kohzoh Imai, Yasuhisa Shinomura, Takashi Tokino

CANCER SCIENCE ( BLACKWELL PUBLISHING )  98 ( 1 ) 88 - 95  2007.01  [Refereed]

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Epigenetic gene inactivation plays a key role in the development of various types of cancer. Using methylated CpG island amplification coupled with representational difference analysis to identify genes inactivated by DNA methylation in gastric cancer, we identified seven DNA fragments corresponding to the 5' CpG islands of the affected genes. One of the clones recovered was identical to the 5' flanking region of DFNA5, a gene previously shown to be associated with deafness and induced by DNA damage. Further analysis revealed that DFNA5 is expressed in normal tissues but is downregulated in gastric cancer cell lines due to methylation of the region around its transcription start site. Treating gastric cancer cells that lacked DFNA5 expression with a methyltransferase inhibitor, 5-aza-2'-deoxycytidine, restored the gene's expression. Methylation of DFNA5 was detected in 50% of primary gastric tumors, and was correlated with positivity for Epstein-Barr virus and the absence of metastasis. Moreover, introduction of exogenous DFNA5 into silenced cells suppressed colony formation. Taken together, these data suggest that the silencing of DFNA5 occurs frequently in gastric cancer and may play a key role in development and progression of the disease.

DOI PubMed

Epigenetics in gastroenterological cancer and prospects for translational research

Hiromu Suzuki, Minoru Toyota, Yasuhisa Shinomura, Kohzoh Imai

Japanese Journal of Gastroenterology   104 ( 9 ) 1319 - 1328  2007  [Refereed]

DOI PubMed

Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer

Nojima M, Suzuki H, Toyota M, Watanabe Y, Maruyama R, Sasaki S, Sasaki Y, Mita H, Nishikawa N, Yamaguchi K, Hirata K, Itoh F, Tokino T, Mori M, Imai K, Shinomura Y

Oncogene   26   4699 - 4713  2007  [Refereed]

DOI

Genomic screening for genes silenced by DNA methylation in multiple myeloma

Yasui, Hiroshi, Toyota, Minoru, Maruyama, Reo, Tarasawa, Isao, Suzuki, Hiromu, Hayashi, Toshiaki, Sakai, Hajime, Ishida, Tadao, Asaoku, Hideki, Tokino, Takashi, Imai, Kohzoh, Shinomura, Yasuhisa

TUMOR BIOLOGY ( KARGER )  28   78 - 78  2007  [Refereed]