title: MicroRNA-152 targets DNA methyltransferase 1 in NiS-transformed cells via a feedback mechanism.
abstract: Nickel (Ni) compounds are well-recognized human carcinogens, yet the molecular mechanisms by which they cause human cancer are still not well understood. MicroRNAs (miRNAs), which are small non-coding RNAs, are involved in diverse biological functions and carcinogenesis. In previous study, we identified upregulation of DNA methyltransferase 1 (DNMT1) expression in nickel sulfide (NiS)-transformed human bronchial epithelial (16HBE) cells. Here, we investigated whether some miRNAs are aberrantly expressed and targets DNMT1 in NiS-transformed cells. Our results showed that the expression of miRNA-152 (miR-152) was specifically downregulated in NiS-transformed cells via promoter DNA hypermethylation, whereas ectopic expression of miR-152 in NiS-transformed cells resulted in a marked reduction of DNMT1 expression. Further experiments revealed that miR-152 directly downregulated DNMT1 expression by targeting the 3' untranslated regions of its transcript. Interestingly, treatment of DNMT inhibitor, 5-aza-2-deoxycytidine, or depletion of DNMT1 led to increased miR-152 expression by reversion of promoter hypermethylation, DNMT1 and MeCP2 binding to miR-152 promoter in NiS-transformed cells. Moreover, inhibition of miR-152 expression in 16HBE cells could increase DNMT1 expression and result in an increase in DNA methylation, DNMT1 and MeCP2 binding to miR-152 promoter, indicating an interaction between miR-152 and DNMT1 is regulated by a double-negative circuit. Furthermore, ectopic expression of miR-152 in NiS-transformed cells led to a significant decrease of cell growth. Conversely, inhibition of miR-152 expression in 16HBE cells significantly increased cell growth. Taken together, these observations demonstrate a crucial functional crosstalk between miR-152 and the DNMT1 via a feedback loop involved in NiS-induced malignant transformation.
authors.affiliation: Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical College, Guangdong Provincial Key Laboratory of Urology, 1 Kangda Road,  Guangzhou 510230, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Ji
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Jianhui
authors.initials: J
authors.lastname: Yuan
authors.forename: Linqing
authors.initials: L
authors.lastname: Yang
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.forename: Defeng
authors.initials: D
authors.lastname: Qi
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Duan
authors.forename: Aiguo
authors.initials: A
authors.lastname: Xuan
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Zhang
authors.forename: Jiachun
authors.initials: J
authors.lastname: Lu
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Zhuang
authors.forename: Guohua
authors.initials: G
authors.lastname: Zeng
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D025461:Feedback, Physiological / Q000187:drug effects*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009532:Nickel / Q000009:adverse effects*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020413:3' Untranslated Regions; D002273:Carcinogens; D035683:MicroRNAs; D012333:RNA, Messenger; D009532:Nickel; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C017558:nickel sulfide