p53 Regulates Nuclear GSK-3 Levels Through miR-34-mediated Axin2 Suppression in Colorectal Cancer Cells

Cell Cycle. 2013 May 15;12(10):1578-87. doi: 10.4161/cc.24739. Epub 2013 Apr 25.

Abstract

p53 is a bona fide tumor suppressor gene whose loss of function marks the most common genetic alteration in human malignancy. Although the causal link between loss of p53 function and tumorigenesis has been clearly demonstrated, the mechanistic links by which loss of p53 potentiates oncogenic signaling are not fully understood. Recent evidence indicates that the microRNA-34 (miR-34) family, a transcriptional target of the p53, directly suppresses a set of canonical Wnt genes and Snail, resulting in p53-mediated suppression of Wnt signaling and the EMT process. In this study, we report that p53 regulates GSK-3β nuclear localization via miR-34-mediated suppression of Axin2 in colorectal cancer. Exogenous miR-34a decreases Axin2 UTR-reporter activity through multiple binding sites within the 5' and 3' UTR of Axin2. Suppression of Axin2 by p53 or miR-34 increases nuclear GSK-3β abundance and leads to decreased Snail expression in colorectal cancer cells. Conversely, expression of the non-coding UTR of Axin2 causes depletion of endogenous miR-34 via the miR-sponge effect together with increased Axin2 function, supporting that the RNA-RNA interactions with Axin2 transcripts act as an endogenous decoy for miR-34. Further, RNA transcripts of miR-34 target were correlated with Axin2 in clinical data set of colorectal cancer patients. Although the biological relevance of nuclear GSK-3 level has not been fully studied, our results demonstrate that the tumor suppressor p53/miR-34 axis plays a role in regulating nuclear GSK-3 levels and Wnt signaling through the non-coding UTR of Axin2 in colorectal cancer.

Keywords: Axin2; GSK-3; Snail; epithelial-mesenchymal transition (EMT); miR-34); microRNA-34 (miRNA-34; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • 5' Untranslated Regions
  • Antibiotics, Antineoplastic / pharmacology
  • Axin Protein / antagonists & inhibitors
  • Axin Protein / genetics
  • Axin Protein / metabolism*
  • Binding Sites
  • Cell Line, Tumor
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Doxorubicin / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glycogen Synthase Kinase 3 / metabolism*
  • HCT116 Cells
  • Humans
  • MicroRNAs / metabolism*
  • RNA Interference
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Snail Family Transcription Factors
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / metabolism*
  • Wnt Signaling Pathway

Substances

  • 3' Untranslated Regions
  • 5' Untranslated Regions
  • AXIN2 protein, human
  • Antibiotics, Antineoplastic
  • Axin Protein
  • MIRN34 microRNA, human
  • MicroRNAs
  • RNA, Messenger
  • RNA, Small Interfering
  • Snail Family Transcription Factors
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Doxorubicin
  • Glycogen Synthase Kinase 3