p53 regulates nuclear GSK-3 levels through miR-34-mediated Axin2 suppression in colorectal cancer cells

Nam Hee Kim, Yong Hoon Cha, Shi Eun Kang, Yoonmi Lee, Inhan Lee, So Young Cha, Joo Kyung Ryu, Jung Min Na, Changbum Park, Ho Geun Yoon, Gyeong Ju Park, Jong In Yook, Hyun Sil Kim

Research output: Contribution to journalArticlepeer-review

89 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1578-1587
Number of pages10
JournalCell Cycle
Volume12
Issue number10
DOIs
Publication statusPublished - 2013 May 15

Bibliographical note

Funding Information:
We thank E. Tunkle for preparation of the manuscript. This work was supported by grants from the National Research Foundation of Korea (2012-0000128, 2011-0031396, 2012M3A9B2052523), a grant from the National R&D Program for Cancer Control (1020110).

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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