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  1. Article ; Online: Oncogenic roles of the SETDB2 histone methyltransferase in gastric cancer.

    Nishikawaji, Taketo / Akiyama, Yoshimitsu / Shimada, Shu / Kojima, Kazuyuki / Kawano, Tatsuyuki / Eishi, Yoshinobu / Yuasa, Yasuhito / Tanaka, Shinji

    Oncotarget

    2016  Volume 7, Issue 41, Page(s) 67251–67265

    Abstract: SETDB2 is a histone H3 lysine 9 (H3K9) tri-methyltransferase that is involved in transcriptional gene silencing. Since it is still unknown whether SETDB2 is linked to carcinogenesis, we studied alterations and functions of SETDB2 in human gastric cancers ...

    Abstract SETDB2 is a histone H3 lysine 9 (H3K9) tri-methyltransferase that is involved in transcriptional gene silencing. Since it is still unknown whether SETDB2 is linked to carcinogenesis, we studied alterations and functions of SETDB2 in human gastric cancers (GCs). SETDB2 protein was highly expressed in 30 of 72 (41.7%) primary GC tissues compared with their normal counterparts by immunohistochemistry. SETDB2 overexpression was significantly associated with the late stage of GCs (P<0.05) and poor prognosis of GC patients (P<0.05). The GC cell lines with SETDB2 knockdown and overexpression significantly decreased and increased cell proliferation, migration and invasion, respectively (P<0.05). Knockdown of SETDB2 in MKN74 and MKN45 cells reduced global H3K9 tri-methylation (me3) levels. Microarray analysis indicated that expression of WWOX and CADM1, tumor suppressor genes, was significantly enhanced in MKN74 cells after SETDB2 knockdown. Chromatin immunoprecipitation assays showed that the H3K9me3 levels at the promoter regions of these two genes corresponded to the SETDB2 expression levels in GC cells. Moreover, ectopic SETDB2 protein was recruited to their promoter regions. Our data suggest that SETDB2 is associated with transcriptional repression of WWOX and CADM1, and hence overexpression of SETDB2 may contribute to GC progression.
    Language English
    Publishing date 2016-10-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.11625
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A subset of diffuse-type gastric cancer is susceptible to mTOR inhibitors and checkpoint inhibitors.

    Fukamachi, Hiroshi / Kim, Seon-Kyu / Koh, Jiwon / Lee, Hye Seung / Sasaki, Yasushi / Yamashita, Kentaro / Nishikawaji, Taketo / Shimada, Shu / Akiyama, Yoshimitsu / Byeon, Sun-Ju / Bae, Dong-Hyuck / Okuno, Keisuke / Nakagawa, Masatoshi / Tanioka, Toshiro / Inokuchi, Mikito / Kawachi, Hiroshi / Tsuchiya, Kiichiro / Kojima, Kazuyuki / Tokino, Takashi /
    Eishi, Yoshinobu / Kim, Yong Sung / Kim, Woo Ho / Yuasa, Yasuhito / Tanaka, Shinji

    Journal of experimental & clinical cancer research : CR

    2019  Volume 38, Issue 1, Page(s) 127

    Abstract: Background: Mechanistic target of rapamycin (mTOR) pathway is essential for the growth of gastric cancer (GC), but mTOR inhibitor everolimus was not effective for the treatment of GCs. The Cancer Genome Atlas (TCGA) researchers reported that most ... ...

    Abstract Background: Mechanistic target of rapamycin (mTOR) pathway is essential for the growth of gastric cancer (GC), but mTOR inhibitor everolimus was not effective for the treatment of GCs. The Cancer Genome Atlas (TCGA) researchers reported that most diffuse-type GCs were genomically stable (GS). Pathological analysis suggested that some diffuse-type GCs developed from intestinal-type GCs.
    Methods: We established patient-derived xenograft (PDX) lines from diffuse-type GCs, and searched for drugs that suppressed their growth. Diffuse-type GCs were classified into subtypes by their gene expression profiles.
    Results: mTOR inhibitor temsirolimus strongly suppressed the growth of PDX-derived diffuse-type GC-initiating cells, which was regulated via Wnt-mTOR axis. These cells were microsatellite unstable (MSI) or chromosomally unstable (CIN), inconsistent with TCGA report. Diffuse-type GCs in TCGA cohort could be classified into two clusters, and GS subtype was major in cluster I while CIN and MSI subtypes were predominant in cluster II where PDX-derived diffuse-type GC cells were included. We estimated that about 9 and 55% of the diffuse-type GCs in cluster II were responders to mTOR inhibitors and checkpoint inhibitors, respectively, by identifying PIK3CA mutations and MSI condition in TCGA cohort. These ratios were far greater than those of diffuse-type GCs in cluster I or intestinal-type GCs. Further analysis suggested that diffuse-type GCs in cluster II developed from intestinal-type GCs while those in cluster I from normal gastric epithelial cells.
    Conclusion: mTOR inhibitors and checkpoint inhibitors might be useful for the treatment of a subset of diffuse-type GCs which may develop from intestinal-type GCs.
    MeSH term(s) Animals ; Humans ; Mice ; Microsatellite Instability ; Stomach Neoplasms/drug therapy ; Stomach Neoplasms/pathology ; TOR Serine-Threonine Kinases/antagonists & inhibitors
    Chemical Substances MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1)
    Language English
    Publishing date 2019-03-12
    Publishing country England
    Document type Journal Article
    ZDB-ID 803138-1
    ISSN 1756-9966 ; 0392-9078
    ISSN (online) 1756-9966
    ISSN 0392-9078
    DOI 10.1186/s13046-019-1121-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2065: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Reduced expression of SET7/9, a histone mono-methyltransferase, is associated with gastric cancer progression.

    Akiyama, Yoshimitsu / Koda, Yuki / Byeon, Sun-Ju / Shimada, Shu / Nishikawaji, Taketo / Sakamoto, Ayuna / Chen, Yingxuan / Kojima, Kazuyuki / Kawano, Tatsuyuki / Eishi, Yoshinobu / Deng, Dajun / Kim, Woo Ho / Zhu, Wei-Guo / Yuasa, Yasuhito / Tanaka, Shinji

    Oncotarget

    2016  Volume 7, Issue 4, Page(s) 3966–3983

    Abstract: SET7/9, a histone methyltransferase, has two distinct functions for lysine methylation. SET7/9 methylates non-histone proteins, such as p53, and participates in their posttranslational modifications. Although SET7/9 transcriptionally activate the genes ... ...

    Abstract SET7/9, a histone methyltransferase, has two distinct functions for lysine methylation. SET7/9 methylates non-histone proteins, such as p53, and participates in their posttranslational modifications. Although SET7/9 transcriptionally activate the genes via H3K4 mono-methylation, its target genes are poorly understood. To clarify whether or not SET7/9 is related to carcinogenesis, we studied alterations of SET7/9 in gastric cancers (GCs). Among the 376 primary GCs, 129 cases (34.3%) showed loss or weak expression of SET7/9 protein compared to matched non-cancerous tissues by immunohistochemistry. Reduced SET7/9 expression was significantly correlated with clinical aggressiveness and worse prognosis. Knockdown of SET7/9 in GC cells markedly increased cell proliferation, migration and invasion. Expression of SREK1IP1, PGC and CCDC28B were inhibited in GC cells with SET7/9 knockdown, while matrix metalloproteinase genes (MMP1, MMP7 and MMP9) were activated. SET7/9 bound and mono-methylated H3K4 at the region of the approximately 4-6 kb upstream from the SREK1IP1 transcriptional start site and the promoters of PGC and CDC28B. Cell proliferation, migration and invasion, and expression of three MMPs were increased in GC cells with SREK1IP knockdown, which were similar to those of SET7/9 knockdown. These data suggest that SET7/9 has tumor suppressor functions, and loss of SET7/9 may contribute to gastric cancer progression.
    MeSH term(s) Apoptosis ; Blotting, Western ; Cell Proliferation ; Chromatin Immunoprecipitation ; DNA Methylation ; Disease Progression ; Female ; Histone-Lysine N-Methyltransferase/genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Humans ; Immunoenzyme Techniques ; Male ; Middle Aged ; Mutation/genetics ; Neoplasm Invasiveness ; Neoplasm Staging ; Prognosis ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Stomach Neoplasms/enzymology ; Stomach Neoplasms/genetics ; Stomach Neoplasms/pathology ; Tumor Cells, Cultured
    Chemical Substances RNA, Messenger ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; SETD7 protein, human (EC 2.1.1.43)
    Language English
    Publishing date 2016-01-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.6681
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: ARID2 modulates DNA damage response in human hepatocellular carcinoma cells.

    Oba, Atsushi / Shimada, Shu / Akiyama, Yoshimitsu / Nishikawaji, Taketo / Mogushi, Kaoru / Ito, Hiromitsu / Matsumura, Satoshi / Aihara, Arihiro / Mitsunori, Yusuke / Ban, Daisuke / Ochiai, Takanori / Kudo, Atsushi / Asahara, Hiroshi / Kaida, Atsushi / Miura, Masahiko / Tanabe, Minoru / Tanaka, Shinji

    Journal of hepatology

    2017  Volume 66, Issue 5, Page(s) 942–951

    Abstract: Background & aims: Recent genomic studies have identified frequent mutations of AT-rich interactive domain 2 (ARID2) in hepatocellular carcinoma (HCC), but it is not still understood how ARID2 exhibits tumor suppressor activities.: Methods: We ... ...

    Abstract Background & aims: Recent genomic studies have identified frequent mutations of AT-rich interactive domain 2 (ARID2) in hepatocellular carcinoma (HCC), but it is not still understood how ARID2 exhibits tumor suppressor activities.
    Methods: We established the ARID2 knockout human HCC cell lines by using CRISPR/Cas9 system, and investigated the gene expression profiles and biological functions.
    Results: Bioinformatic analysis indicated that UV-response genes were negatively regulated in the ARID2 knockout cells, and they were sensitized to UV irradiation. ARID2 depletion attenuated nucleotide excision repair (NER) of DNA damage sites introduced by exposure to UV as well as chemical compounds known as carcinogens for HCC, benzo[a]pyrene and FeCl
    Conclusions: We provide evidence that ARID2 knockout could contribute to disruption of NER process through inhibiting the recruitment of XPG, resulting in susceptibility to carcinogens and potential hypermutation. These findings have implications for therapeutic targets in cancers harboring ARID2 mutations.
    Lay summary: Recent genomic studies have identified frequent mutations of ARID2, a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, in hepatocellular carcinoma, but it is not still understood how ARID2 exhibits tumor suppressor activities. In current study, we provided evidence that ARID2 knockout could contribute to disruption of DNA repair process, resulting in susceptibility to carcinogens and potential hypermutation. These findings have far-reaching implications for therapeutic targets in cancers harboring ARID2 mutations.
    MeSH term(s) Apoptosis ; Carcinoma, Hepatocellular/genetics ; Cell Line, Tumor ; Computational Biology ; DNA Damage ; DNA Repair ; Humans ; Liver Neoplasms/genetics ; Mutation ; Reactive Oxygen Species/metabolism ; Transcription Factors/physiology ; Ultraviolet Rays
    Chemical Substances ARID2 protein, human ; Reactive Oxygen Species ; Transcription Factors
    Language English
    Publishing date 2017
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 605953-3
    ISSN 1600-0641 ; 0168-8278
    ISSN (online) 1600-0641
    ISSN 0168-8278
    DOI 10.1016/j.jhep.2016.12.026
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2027: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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