EPSIN 3, a novel p53 target, regulates the apoptotic pathway and gastric carcinogenesis

Publication date: March 2017
Source:Neoplasia, Volume 19, Issue 3
Author(s): Jinichi Mori, Chizu Tanikawa, Naomi Ohnishi, Yuki Funauchi, Osamu Toyoshima, Koji Ueda, Koichi Matsuda
BACKGROUND & AIM: p53 activation by cellular stresses induces the transcription of hundreds of its target genes. To elucidate the entire picture of its downstream pathway, we screened a cDNA microarray dataset of adriamycin-treated HCT116 p53^−/− or p53^+/+ cells and identified EPSIN 3 as a novel p53 target. METHODS: Potential p53 binding sequences in the EPSIN 3 locus were evaluated by reporter and CHIP assays. To investigate the role of EPSIN 3 in the p53 downstream pathway, we assessed DNA damage-induced apoptosis in EPSIN 3-knockdown HCT116 cells or Epsin 3-deficient mice. In addition, we evaluated EPSIN 3 expression levels in various tissues, including gastric adenocarcinoma, human gastric mucosa with or without Helicobacter pylori infection, and mouse acute gastritis tissues induced by indomethacin. RESULTS: In response to DNA damage, p53 induced the expression of EPSIN 3 through the p53 binding elements in the EPSIN 3 promoter and the first intron. Knockdown of EPSIN 3 resulted in resistance to DNA damage-induced apoptosis both in vitro and in vivo. EPSIN 3 expression was down-regulated in gastric cancer tissues compared with normal tissues. In addition, Helicobacter pylori infection and indomethacin-induced acute gastritis repressed EPSIN 3 expression in gastric mucosa. CONCLUSIONS: EPSIN 3 is a novel p53 target and a key mediator of apoptosis. Chronic or acute mucosal inflammation as well as p53 inactivation induced down-regulation of EPSIN 3 and subsequently caused apoptosis resistance, which is a hallmark of cancer cells.



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