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

Yuqing Zhang, Jingxuan Yang, Xiaobo Cui, Yong Chen, Vivian F. Zhu, John P. Hagan, Huamin Wang, Xianjun Yu, Sally E. Hodges, Jing Fang, Paul J. Chiao, Craig D. Logsdon, William E. Fisher, F. Charles Brunicardi, Changyi Chen, Qizhi Yao, Martin E. Fernandez-Zapico, Min Li

Research output: Contribution to journalArticle

58 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1322-1334
Number of pages13
JournalEMBO Molecular Medicine
Volume5
Issue number9
DOIs
StatePublished - Sep 1 2013

Keywords

  • MicroRNA-373
  • Pancreatic cancer
  • ZIP4
  • Zinc

ASJC Scopus subject areas

  • Molecular Medicine

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    Zhang, Y., Yang, J., Cui, X., Chen, Y., Zhu, V. F., Hagan, J. P., Wang, H., Yu, X., Hodges, S. E., Fang, J., Chiao, P. J., Logsdon, C. D., Fisher, W. E., Brunicardi, F. C., Chen, C., Yao, Q., Fernandez-Zapico, M. E., & Li, M. (2013). A novel epigenetic CREB-miR-373 axis mediates ZIP4-induced pancreatic cancer growth. EMBO Molecular Medicine, 5(9), 1322-1334. https://doi.org/10.1002/emmm.201302507