title: Epigenetic silencing of DUSP9 induces the proliferation of human gastric cancer by activating JNK signaling.
abstract: Dual-specificity phosphatase 9 (DUSP9) is a strong negative regulator of transcription factor activating kinases (ERK, JNK and p38) in the mitogen-activated protein kinase (MAPK) pathways. The aim of this study was to examine the CpG island methylation status of DUSP9 using bisulfite sequencing PCR (BSP) in gastric cancer (GC). The investigation was conducted on 30 clinical GC samples and selected corresponding tumor-free normal gastric mucosa tissues, using BSP for the determination of the promoter methylation status. The methylation status of the tumor samples was compared to the corresponding tumor-free samples. DUSP9 was silenced by promoter region hypermethylation and G2/M phase arrest was induced by DUSP9 in the MKN-1 GC cell line. MKN-1 proliferation was suppressed by DUSP9 by inhibiting c-Jun, which was induced by JNK signaling. The expression levels of CCND1, c-Jun, CDK4 and CDK6 were upregulated while p21 was downregulated by DUSP9 in MKN-1 cells. However, DUSP9-induced resulted in the regulation of the levels of cycle-related molecules, whivh were inhibited when the JNK inhibitor SP600125 was added. In conclusion, DUSP9 was frequently methylated in human GC and the expression of DUSP9 is silenced by promoter region hypermethylation. The results of this study, combined with previous studies, suggested that therapeutic intervention to increase the expression or activity of DUSP9 may enable the activation of anti-proliferation signals in malignant cells.
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Nursing, Medical School, Huzhou Teachers College, Zhejiang, P.R. China.
authors.forename: Tianmin
authors.initials: T
authors.lastname: Lv
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, P.R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, P.R. China.
authors.forename: Huajun
authors.initials: H
authors.lastname: Ye
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Chemoradiation Oncology, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, P.R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China.
authors.forename: Fa-Chao
authors.initials: FC
authors.lastname: Zhi
mesh_terms: D000873:Anthracenes / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics; D054637:Dual-Specificity Phosphatases / Q000096:biosynthesis / Q000235:genetics*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D000873:Anthracenes; C432165:pyrazolanthrone; D054639:Mitogen-Activated Protein Kinase Phosphatases; C104821:DUSP9 protein, human; D054637:Dual-Specificity Phosphatases