Modulations of DNMT1 and HDAC1 are involved in the OTA-induced cytotoxicity and apoptosis in vitro. (25th December 2017)

• Record Type: Journal Article
• Authors: Zhou, Yajiao; Gan, Fang; Hou, Lili; Zhou, Xuan; Adam Ibrahim, Yassin Abdulrahim; Huang, Kehe
• Is Part Of: Chemico-biological interactions. Volume 278(2017)
• Page Start: 170
• Page End: 178
• Publication Date: 2017-12-25
• Subjects: Ochratoxin A -- DNMT1 -- HDAC1 -- Cytotoxicity -- Apoptosis; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2017.10.020
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Ochratoxin A (OTA) as a fungal metabolite is reported to induce cytotoxicity and apoptosis through the mechanism of oxidative stress. Oxidative stress could induce the epigenetic enzymes modifications. However, whether epigenetic enzymes modifications are involved in OTA-induced cytotoxicity and apoptosis has not been reported until now. Therefore, the objectives of this study were to verify OTA-induced cytotoxicity and apoptosis and to investigate the potential role of epigenetic enzymes in OTA-induced cytotoxicity and apoptosis in PK15 cells. The results demonstrated that OTA at 4 μg/ml treatment for 12 h and 24 h induced cytotoxicity and apoptosis as demonstrated by decreasing cell viability, increasing LDH release, Annexin V/PI staining, Bcl-2/Bax mRNA ratio and apoptotic nuclei in PK15 cells. OTA treatment up-regulated ROS production and down-regulated GSH levels. In addition, OTA treatment activated the epigenetics related enzymes DNA methyltransferase 1 (DNMT1) and Histone deacetylase 1 (HDAC1). Adding DNMT1 inhibitor (5-Aza-2dc) or HDAC1 inhibitor (LBH589) depressed the up-regulation of DNMT1 or HDAC1 expression, the decreases of GSH levels and increases of ROS production induced by OTA, respectively. Furthermore, inhibition of DNMT1 or HDAC1 by their inhibitor reversed the decreases of cell viability and increases of LDH activity and apoptosis induced by OTA, respectively. In conclusion, the observed effects indicate that the critical modulation of DNMT1 and HDAC1 is related to OTA-induced cytotoxicity and apoptosis. Highlights: OTA treatment activate the epigenetics related enzymes DNMT1 and HDAC1 in PK15 cells. DNMT1 and HDAC1 are involved in OTA induced cytotoxicity and apoptosis. Inhibition of DNMT1 or HDAC1 reversed the cytotoxicity and apoptosis induced by OTA.