title: Reduced expression of SET7/9, a histone mono-methyltransferase, is associated with gastric cancer progression.
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.
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Akiyama
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Koda
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Jongno-gu, Seoul 110-799, Korea.
authors.forename: Sun-Ju
authors.initials: SJ
authors.lastname: Byeon
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Shimada
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Taketo
authors.initials: T
authors.lastname: Nishikawaji
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Ayuna
authors.initials: A
authors.lastname: Sakamoto
authors.affiliation: Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China.
authors.forename: Yingxuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Surgical Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kojima
authors.affiliation: Department of Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Kawano
authors.affiliation: Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Eishi
authors.affiliation: Division of Cancer Etiology, Peking University Cancer Hospital and Institute, Beijing 100142, China.
authors.forename: Dajun
authors.initials: D
authors.lastname: Deng
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Jongno-gu, Seoul 110-799, Korea.
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Zhu
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Yuasa
authors.affiliation: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human
keywords: H3K4me1; SET7/9; SREK1IP1; gastric cancer; histone methyltransferase