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CITED2 is activated in ulcerative colitis and induces p53-dependent apoptosis in response to butyric acid

  • Original Article—Alimentary Tract
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Abstract

Background

In ulcerative colitis (UC), Fusobacterium varium is significantly detected in patients’ mucosa, and butyric acid (BA), abundantly produced by the bacterium, activates the p53 system and induces epithelial apoptosis, as we previously reported. However, factors active in the link between BA and p53 have yet to be clarified. Here, we identified a gene activated by BA specifically in UC-associated cancer cell lines and ascertained the mechanism of its activation of p53.

Methods

cDNA microarray analysis based on the Percellome (per cell normalization) method was performed on BA-stimulated UC-associated cancers and sporadic colorectal cancer cell lines under conditions mimicking colonic epithelium UC. For validation of microarray results, molecular, biochemical, and histopathological analyses were performed.

Results

We found the CBP/p300-interacting transactivator with glutamic acid/asparagine-rich carboxy-terminal domain 2 (CITED2) to be specifically upregulated in UC-associated cancer cell lines by BA treatment, at both mRNA and protein expression levels. CITED2 could be shown to induce p53 acetylation and p53-dependent apoptosis, accompanied by binding of CBP/p300. BA-dependent apoptosis was suppressed by an inhibitor of monocarboxylate transporter-1 and an siRNA for p53. In inflammatory foci of UC, histologically evident inflammatory activity and CITED2 expression were significantly correlated.

Conclusions

CITED2 was identified as UC-associated protein by cDNA microarray based on the Percellome method under UC-mimicking conditions in vitro. CITED2 activation may induce mucosal apoptosis and erosion by activating p53 and thus play a critical role in linking enteric bacteria with mucosal inflammation in UC.

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Abbreviations

BA:

Butyric acid

CITED2:

CBP/p300-interacting transactivator with glutamic acid/asparagine-rich carboxy-terminal domain 2

4CHC:

4-Hydroxycinnamate

IL-10:

Interleukin-10

MCT1:

Monocarboxylate transporter-1

q-RT-PCR:

Quantitative reverse transcription PCR

sCRC:

Sporadic colorectal cancer

UC:

Ulcerative colitis

UCCA:

Ulcerative colitis-associated cancer

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Acknowledgments

The authors appreciate the technical assistance of Ms. Y. Numata and would like to thank Dr. M. Moore for revising the English of the manuscript. This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, Health Sciences Research Grants H18-Kagaku-Ippan-001 from the Ministry of Health, Labour and Welfare, Japan, Grants-in-Aid from Kitasato University Graduate School of Medical Sciences and Kanagawa Nanbyo Foundation.

Conflicts of interest

The authors disclose no conflicts with this work.

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Authors and Affiliations

  1. Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan

    Tsutomu Yoshida, Tsukasa Sekine, Tetuo Mikami & Isao Okayasu

  2. Division of Cellular and Molecular Toxicology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-5801, Japan

    Ken-ichi Aisaki & Jun Kanno

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  1. Tsutomu Yoshida
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  2. Tsukasa Sekine
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  6. Isao Okayasu
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Correspondence to Tsutomu Yoshida.

Additional information

The GeneChip data have been deposited in the Percellome project site (http://www.nihs.go.jp/tox/TtgPublication.htm) and are accessible with no restriction.

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Yoshida, T., Sekine, T., Aisaki, Ki. et al. CITED2 is activated in ulcerative colitis and induces p53-dependent apoptosis in response to butyric acid. J Gastroenterol 46, 339–349 (2011). https://doi.org/10.1007/s00535-010-0355-9

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  • DOI: https://doi.org/10.1007/s00535-010-0355-9

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