title: Regulation of tissue factor pathway inhibitor-2 (TFPI-2) expression by lysine-specific demethylase 1 and 2 (LSD1 and LSD2).
abstract: Tissue factor pathway inhibitor-2 (TFPI-2) is a major inhibitor of extracellular matrix degradation. Decreases in TFPI-2 contribute to malignant tumor cell production, and TFPI-2 is a presumed tumor suppressor. TFPI-2 gene transcription is regulated by two epigenetic mechanisms: DNA methylation of the promoter and K4 methylation of histone 3 (H3). Lysine-specific demethylase 1 (LSD1) and LSD2 demethylate H3K4me2/1. LSD1 has been implicated in TFPI-2 regulation through both epigenetic mechanisms, but the involvement of LSD2 remains unknown. We prepared a monoclonal anti-LSD2 antibody that clearly distinguishes LSD2 from LSD1. Knockdown of LSD1 or LSD2 by siRNAs increased TFPI-2 protein and mRNA. Simultaneous knockdown of both LSD1 and LSD2 showed additive effects. Bisulfite sequencing revealed that CpG sites in the TFPI-2 promoter region were unmethylated. These results indicate that LSD2 also contributes to TFPI-2 regulation through histone modification, and that further studies of the involvement of LSD2 in tumor malignancy are warranted.
authors.affiliation: a Graduate School of Bio-Science , Nagahama Institute of Bio-Science and Technology , Nagahama , Japan.
authors.forename: Koshiki
authors.initials: K
authors.lastname: Mino
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishimura
authors.forename: Shogo
authors.initials: S
authors.lastname: Ninomiya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tujii
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Matsumori
authors.forename: Mie
authors.initials: M
authors.lastname: Tsuchida
authors.forename: Miho
authors.initials: M
authors.lastname: Hosoi
authors.forename: Koichi
authors.initials: K
authors.lastname: Koseki
authors.forename: Shuichi
authors.initials: S
authors.lastname: Wada
authors.forename: Makoto
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Sasaki
authors.forename: Yukie
authors.initials: Y
authors.lastname: Murakami-Yamaguchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Narita
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyata
authors.forename: Tamio
authors.initials: T
authors.lastname: Mizukami
mesh_terms: D063646:Carcinogenesis; D019175:DNA Methylation / Q000187:drug effects; D004706:Endodeoxyribonucleases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000235:genetics*; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D006023:Glycoproteins; D006657:Histones; C021240:tissue-factor-pathway inhibitor 2; D056466:Histone Demethylases; C495195:KDM1A protein, human; C485421:DNASE1L3 protein, human; D004706:Endodeoxyribonucleases
keywords: histone H3K4 methylation; lysine-specific demethylases (LSD1 and LSD2); monoclonal anti-LSD2 antibody; tissue factor pathway inhibitor-2 (TFPI-2)