title: A novel epigenetic CREB-miR-373 axis mediates ZIP4-induced pancreatic cancer growth.
abstract: Changes in the intracellular levels of the essential micronutrient zinc have been implicated in multiple diseases including pancreatic cancer; however, the molecular mechanism is poorly understood. Here, we report a novel mechanism where increased zinc mediated by the zinc importer ZIP4 transcriptionally induces miR-373 in pancreatic cancer to promote tumour growth. Reporter, expression and chromatin immunoprecipitation assays demonstrate that ZIP4 activates the zinc-dependent transcription factor CREB and requires this transcription factor to increase miR-373 expression through the regulation of its promoter. miR-373 induction is necessary for efficient ZIP4-dependent enhancement of cell proliferation, invasion, and tumour growth. Further analysis of miR-373 in vivo oncogenic function reveals that it is mediated through its negative regulation of TP53INP1, LATS2 and CD44. These results define a novel ZIP4-CREB-miR-373 signalling axis promoting pancreatic cancer growth, providing mechanistic insights explaining in part how a zinc transporter functions in cancer cells and may have broader implications as inappropriate regulation of intracellular zinc levels plays an important role in many other diseases.
authors.affiliation: Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jingxuan
authors.initials: J
authors.lastname: Yang
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Cui
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Vivian F
authors.initials: VF
authors.lastname: Zhu
authors.forename: John P
authors.initials: JP
authors.lastname: Hagan
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
authors.forename: Xianjun
authors.initials: X
authors.lastname: Yu
authors.forename: Sally E
authors.initials: SE
authors.lastname: Hodges
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Chiao
authors.forename: Craig D
authors.initials: CD
authors.lastname: Logsdon
authors.forename: William E
authors.initials: WE
authors.lastname: Fisher
authors.forename: F Charles
authors.initials: FC
authors.lastname: Brunicardi
authors.forename: Changyi
authors.initials: C
authors.lastname: Chen
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Yao
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.forename: Min
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D064593:Heterografts; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000503:physiopathology*; D015032:Zinc / Q000378:metabolism*
chemical_list: C115163:CREB1 protein, human; D027682:Cation Transport Proteins; D017362:Cyclic AMP Response Element-Binding Protein; C527114:MIRN373 microRNA, human; D035683:MicroRNAs; C486791:SLC39A4 protein, human; D015032:Zinc
keywords: ZIP4; microRNA-373; pancreatic cancer; zinc