Oncogenic roles of the SETDB2 histone methyltransferase in gastric cancer.

// Taketo Nishikawaji 1 , Yoshimitsu Akiyama 1 , Shu Shimada 1 , Kazuyuki Kojima 2 , Tatsuyuki Kawano 3 , Yoshinobu Eishi 4 , Yasuhito Yuasa 1 , Shinji Tanaka 1 1 Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan 2 Department of Surgical Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan 3 Department of Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan 4 Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan Correspondence to: Shinji Tanaka, email: tanaka.monc@tmd.ac.jp Yoshimitsu Akiyama, email: yakiyama.monc@tmd.ac.jp Keywords: gastric cancer, histone methyltransferase, H3K9me3, SETDB2 Received: March 18, 2016     Accepted: August 11, 2016     Published: August 26, 2016 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.