Reduced expression of SET7/9, a histone mono-methyltransferase, is associated with gastric cancer progression
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Yoshimitsu Akiyama1, Yuki Koda1, Sun-ju Byeon2, Shu Shimada1, Taketo Nishikawaji1, Ayuna Sakamoto1, Yingxuan Chen3, Kazuyuki Kojima4, Tatsuyuki Kawano5, Yoshinobu Eishi6, Dajun Deng7, Woo Ho Kim2, Wei-Guo Zhu8, Yasuhito Yuasa1, Shinji Tanaka1
1Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
2Department of Pathology, Seoul National University College of Medicine, Jongno-gu, Seoul 110-799, Korea
3Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
4Department of Surgical Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
5Department of Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
6Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
7Division of Cancer Etiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
8Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China
Yoshimitsu Akiyama, e-mail: email@example.com
Keywords: gastric cancer, histone methyltransferase, H3K4me1, SET7/9, SREK1IP1
Received: September 03, 2015 Accepted: November 25, 2015 Published: December 19, 2015
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.
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