title: Role of NSD1 in H2O2-induced GSTM3 suppression.
abstract: Nuclear receptor-binding SET domain-containing protein 1 (NSD1) has been proved to act as a histone methyltransferase and a transcription co-factor to regulate gene expression. However, the role of NSD1 in oxidative stress remains poorly understood. In the present study, we focused on the NSD1 regulation of antioxidant enzyme gene glutathione S-transferase M3 (GSTM3) expression in response to oxidative stress. H2O2 treatment caused the decrease of both NSD1 and GSTM3 expression, and the depletion of NSD1 expression by specific siRNA reversed the H2O2-reduced GSTM3 expression. Furthermore, we investigated NSD1 modulating the transcription of GSTM3 promoter with -63A/C polymorphism closed to TATA box in response to H2O2 by luciferase and in vitro or in vivo DNA-protein binding assays. The promoter activity of GSTM3 with -63A was higher than -63C, and was increased or decreased by the overexpression or depletion of NSD1, but -63C was not influenced. H2O2 repressed the promoter activity of GSTM3 with -63A more than -63C, and the depletion of NSD1 expression weakened H2O2 inhibition on the -63A promoter, but augmented H2O2 inhibition on the -63C promoter. In addition, NSD1 interacted with RNAPII and bound to GSTM3 -63A/C TATA box, with higher binding affinity to -63A than to -63C. These data indicated that NSD1 implicated in H2O2-induced oxidative stress, and H2O2-induced NSD1 suppression resulted in the decrease of GSTM3 expression through the -63A/C TATA box.
authors.affiliation: Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China; Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China.
authors.forename: Guoming
authors.initials: G
authors.lastname: Chu
authors.affiliation: Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China; Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China; Department of Medical Genetics, China Medical University, Shenyang, Liaoning, China. Electronic address: yyzhao@sj-hospital.org.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism*; D057809:HEK293 Cells; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D016385:TATA Box / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D000975:Antioxidants; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D006861:Hydrogen Peroxide; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C113272:NSD1 protein, human; C483009:GSTM3 protein, human; D005982:Glutathione Transferase
keywords: Glutathione S-transferase M3; Hydrogen peroxide; Nuclear receptor-binding SET domain-containing protein 1; Oxidative stress; Polymorphism; RNA polymerase II