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Cell Mol Gastroenterol Hepatol. 2016 Jan;2(1):63-76.e5. Epub 2015 Oct 13.

Reduction of p53 by knockdown of the UGT1 locus in colon epithelial cells causes an increase in tumorigenesis.

Author information

1
Laboratory of Environmental Toxicology, Department of Chemistry & Biochemistry and Pharmacology, UCSD, La Jolla, CA, 92023; Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China, 210009.
2
Laboratory of Environmental Toxicology, Department of Chemistry & Biochemistry and Pharmacology, UCSD, La Jolla, CA, 92023.
3
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China, 210009.

Abstract

BACKGROUND & AIMS:

The UDP-glucuronosyltransferases (UGTs) are part of the cells machinery that protects the tissues from a toxicant insult by environmental and host cell metabolites. We have investigated the mechanism behind tumor growth and UGT repression.

METHODS:

We initially silenced the Ugt1 locus in human colon cell lines and investigated markers and responses linked to p53 activation. To examine the role of the Ugt1 locus in p53-directed apoptosis and tumorigenesis, experiments were conducted to induce acute colon inflammation and chemical induced colon cancer in mice where we have selectively deleted the Ugt1 locus in the intestinal epithelial cells (Ugt1ΔIEC mice).

RESULTS:

Knockdown of the UGT1A proteins by RNAi in human colon cancer cells and knockout of the Ugt1 locus in intestinal crypt stem cells reduces phosphorylated p53 activation and compromises the ability of p53 to control apoptosis. Targeted deletion of intestinal Ugt1 expression in Ugt1ΔIEC mice represses colon inflammation-induced p53 production and pro-apoptotic protein activation. When we induced colon cancer, the size and number of the tumors were significantly greater in the Ugt1ΔIEC mice when compared to wild type mice. Furthermore, analysis of endoplasmic reticulum (ER) stress-related markers indicated that lack of UGT1A expression causes higher ER stress in intestinal epithelial cells and tissue, which may account for the lower expression of p53.

CONCLUSIONS:

Our results demonstrate that UGT1A expression is required to maintain and sustain p53 activation in stress-induced colon epithelial cells and has a significant impact on p53-mediated apoptosis and tumor suppression, thus protecting the colon tissue from neoplastic transformation.

KEYWORDS:

ER stress; UGT1A; apoptosis; colon cancer

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