A novel epigenetic CREB‐miR‐373 axis mediates ZIP4‐induced pancreatic cancer growth

EMBO Molecular Medicine

Yuqing Zhang²  Jingxuan Yang¹  Xiaobo Cui¹  Yong Chen³  Vivian F. Zhu¹  John P. Hagan¹  Huamin Wang⁵  Xianjun Yu⁶  Sally E. Hodges²  Jing Fang⁸  Paul J. Chiao⁹  Craig D. Logsdon⁴  William E. Fisher²  F. Charles Brunicardi²  Changyi Chen²  Qizhi Yao²  Martin E. Fernandez-Zapico⁷ 

[1] The Vivian L. Smith Department of Neurosurgery, the University of Texas Medical School at Houston, Houston, TX, USA;Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA;Division of Biostatistics, School of Public Health, the University of Texas Health Science Center at Houston, Houston, TX, USA;Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX, USA;Department of Pathology, UT MD Anderson Cancer Center, Houston, TX, USA;Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai, China;Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, USA;The Key Lab of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China;Department of Molecular and Cellular Oncology, UT MD Anderson Cancer Center, Houston, TX, USA

关键词: microRNA‐373;    pancreatic cancer;    zinc;    ZIP4;   

DOI  :  10.1002/emmm.201302507

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

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