Abrogation of Gli3 expression suppresses the growth of colon cancer cells via activation of p53

Han Na Kang, Sang Cheul Oh, Jun Suk Kim, Young A. Yoo

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

p53, the major human tumor suppressor, appears to be related to sonic hedgehog (Shh)-Gli-mediated tumorigenesis. However, the role of p53 in tumor progression by the Shh-Gli signaling pathway is poorly understood. Herein we investigated the critical regulation of Gli3-p53 in tumorigenesis of colon cancer cells and the molecular mechanisms underlying these effects. RT-PCR analysis indicated that the mRNA level of Shh and Gli3 in colon tumor tissues was significantly higher than corresponding normal tissues (P<0.001). The inhibition of Gli3 by treatment with Gli3 siRNA resulted in a clear decrease in cell proliferation and enhanced the level of expression of p53 proteins compared to treatment with control siRNA. The half-life of p53 was dramatically increased by treatment with Gli3 siRNA. In addition, treatment with MG132 blocked MDM2-mediated p53 ubiquitination and degradation, and led to accumulation of p53 in Gli3 siRNA-overexpressing cells. Importantly, ectopic expression of p53 siRNA reduced the ability of Gli3 siRNA to suppress proliferation of those cells compared with the cells treated with Gli3 siRNA alone. Moreover, Gli3 siRNA sensitized colon cancer cells to treatment with anti-cancer agents (5-FU and bevacizumab). Taken together, our studies demonstrate that loss of Gli3 signaling leads to disruption of the MDM2-p53 interaction and strongly potentiate p53-dependent cell growth inhibition in colon cancer cells, indicating a basis for the rational use of Gli3 antagonists as a novel treatment option for colon cancer.

Original languageEnglish
Pages (from-to)539-549
Number of pages11
JournalExperimental Cell Research
Volume318
Issue number5
DOIs
Publication statusPublished - 2012 Mar 10

Fingerprint

Colonic Neoplasms
Small Interfering RNA
Growth
Neoplasms
Carcinogenesis
Cell Proliferation
Ubiquitination
Fluorouracil
Half-Life
Colon
Polymerase Chain Reaction
Messenger RNA
Proteins

Keywords

  • Colon cancer
  • Gli
  • MDM2
  • P53
  • Sonic hedgehog (Shh)

ASJC Scopus subject areas

  • Cell Biology

Cite this

Abrogation of Gli3 expression suppresses the growth of colon cancer cells via activation of p53. / Kang, Han Na; Oh, Sang Cheul; Kim, Jun Suk; Yoo, Young A.

In: Experimental Cell Research, Vol. 318, No. 5, 10.03.2012, p. 539-549.

Research output: Contribution to journalArticle

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