Silencing of CDX2 expression in colon cancer via a dominant repression pathway

被引:87
|
作者
Hinoi, T
Loda, M
Fearon, ER
机构
[1] Univ Michigan, Med Ctr, Div Mol Med & Genet, Dept Internal Med,Sch Med, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA
[4] Univ Michigan, Sch Med, Ctr Canc, Ann Arbor, MI 48109 USA
[5] Harvard Univ, Brigham & Womens Hosp, Dept Pathol, Sch Med, Boston, MA 02115 USA
[6] Harvard Univ, Brigham & Womens Hosp, Dana Farber Canc Inst, Sch Med,Dept Adult Oncol, Boston, MA 02115 USA
关键词
D O I
10.1074/jbc.M307435200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
CDX2 is a caudal-related homeobox transcription factor whose expression in the adult is normally restricted to intestinal epithelium. Mice heterozygous for germ line Cdx2 inactivation develop intestinal polyps, and the lesions lack Cdx2 expression. Prior studies indicate some human colon carcinomas also lack CDX2 expression. To address the role of CDX2 defects in colon cancer development, we analyzed CDX2 expression in 45 primary colorectal carcinomas. Four carcinomas lacked CDX2 expression, and three others showed aberrant cytoplasmic localization of CDX2, although no significant CDX2 gene defects were seen in the seven tumors. Marked reductions in CDX2 transcript and protein levels were seen in five of 13 colorectal cell lines, and nuclear run-off data indicated reduced transcription was a major factor in CDX2 silencing. Treatment with the DNA demethylating agent 5-aza- 2'-deoxycytidine and/or the histone deacetylase inhibitor trichostatin A did not restore CDX2 expression in CDX2-negative lines. However, consistent with a role for dominant repression mechanisms in CDX2 silencing, all somatic cell hybrids resulting from pairwise fusions between colon cancer lines with intact CDX2 expression and lines lacking CDX2 had reduced CDX2 transcripts and protein. A roughly 9.5-kb 5'-flanking region from the human CDX2 gene contained key cis elements for regulating transcription in colon cancer cells. Restoration of CDX2 expression suppressed proliferation and soft agar growth in the CDX2-negative HT-29 colon cancer cell line. Our findings suggest CDX2 inactivation in colon cancer results from defects in trans-acting pathways regulating CDX2 transcription, and CDX2 silencing contributes to the altered phenotype of some colorectal cancers.
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收藏
页码:44608 / 44616
页数:9
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