Reduced expression of SET7/9, a histone mono-methyltransferase, is associated with gastric cancer progression.

// Yoshimitsu Akiyama 1 , Yuki Koda 1 , Sun-ju Byeon 2 , Shu Shimada 1 , Taketo Nishikawaji 1 , Ayuna Sakamoto 1 , Yingxuan Chen 3 , Kazuyuki Kojima 4 , Tatsuyuki Kawano 5 , Yoshinobu Eishi 6 , Dajun Deng 7 , Woo Ho Kim 2 , Wei-Guo Zhu 8 , Yasuhito Yuasa 1 , Shinji Tanaka 1 1 Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan 2 Department of Pathology, Seoul National University College of Medicine, Jongno-gu, Seoul 110-799, Korea 3 Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China 4 Department of Surgical Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan 5 Department of Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan 6 Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan 7 Division of Cancer Etiology, Peking University Cancer Hospital and Institute, Beijing 100142, China 8 Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China Correspondence to: Yoshimitsu Akiyama, e-mail: yakiyama.monc@tmd.ac.jp Keywords: gastric cancer, histone methyltransferase, H3K4me1, SET7/9, SREK1IP1 Received: September 03, 2015      Accepted: November 25, 2015      Published: December 19, 2015 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 S REK1IP1, 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.