Cited 1 is a novel colorectal cancer gene whose deficiency inhibits the growth of colorectal cancer [Abstract]

Song, F., Phesse, Toby J., Jenkins, J., Clarke, Alan Richard ORCID: https://orcid.org/0000-0002-4281-426X and Watson, A. J. M. 2009. Cited 1 is a novel colorectal cancer gene whose deficiency inhibits the growth of colorectal cancer [Abstract]. Gut 58 (S1) , A3.

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Abstract

Introduction: APC gene mutation is one of the early genetic lesions in the pathogenesis of colorectal cancer. To investigate the primary consequences of APC loss in the intestine, a conditional knock-out mouse model has been developed. We have shown that most of the genes that are deregulated following deletion of APC in mouse intestinal epithelium are also deregulated in human colorectal cancer. We found that Cited1 (CBP/p300-interacting transactivators with glutamic acid [E]/aspartic acid [D]-rich carboxyl-terminal domain, 1) is over-expressed 2.74-fold (n = 40, p<0.00001) in human colorectal cancers compared to adjacent uninvolved colonic mucosa. Little is known about Cited1 but has been characterised as a non-DNA binding transcriptional co-factor. It has been implicated in embryogenesis and breast and thyroid carcinogenesis. These preliminary data suggested that Cited1 may be involved in colorectal carcinogenesis. Aims and Methods: We investigated the effects of Cited1 deficiency on colorectal carcinogenesis both in vivo and in vitro. ApcMin/+Cited1+/+, ApcMin/+Cited1−/+and Apc Min/+Cited1−/Y mice were generated by crossing Cited1 null mice onto an ApcMin/+background. Semi-QPCR was performed to characterise recombined Cited1 expression in the adenomas taken from the three cohorts. siRNA was transfected into human colon cancer cell lines HT29 and HCT116 to reduce Cited1 expression (mRNA expression was detected by taqman QPCR). Cell survival and proliferation post transfection were measured by clonogenic and SRB assays. Results: As Cited1 is X-linked, the homozygous null mice are all males. The median life span of ApcMin/+Cited1+/+(n = 17) was 250 days, which was significantly increased to 333 days on ApcMin/+Cited1−/+ (n = 20, p = 0.0008), and further to 378 days on ApcMin/+Cited1Y/− (n = 6, p = 0.0004). Cited1 expression was reduced by target siRNA by 80% in HT29 (n = 3, p = 0.018) and 95% in HCT116 cells (n = 4, p = 0.007). In clonogenic assay, both cell lines were less viable when treated with target Cited1 siRNA than when treated with non-target siRNA (n = 6, p<0.002), suggesting that loss of Cited1 increases cell death. Cell proliferation was most dramatically reduced 5 days post transfection in HT29 (44% reduction, n = 6, p<0.001) and 4 days in HCT116 cells (34% reduction, n = 6, p<0.001). Conclusion: Cited1 is over-expressed in human colorectal cancer, which implies that Cited1 is involved in intestinal carcinogenesis. Our data demonstrates that deficiency of one or both Cited1 alleles leads to a stepwise increase in life span of MIN mice. In cultured human colon cancer cells, reduction in expression of Cited1 increases cell death and significantly reduces cell proliferation. We conclude that Cited1 is a previously unrecognised component of colorectal carcinogenesis.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Additional Information:	Abstract 0-07 for BSG inflammatory bowel disease symposium
Publisher:	BMJ Publishing Group
ISSN:	0017-5749
Last Modified:	02 Dec 2022 11:49
URI:	https://orca.cardiff.ac.uk/id/eprint/8782

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