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APC mutations lead to cytokinetic failures in vitro and tetraploid genotypes in Min mice.

ABSTRACT: Previous research has proposed that genomic instability contributes to cancer progression, with its initiation linked to tetraploid cell formation (Duesberg, P., and R. Li. 2003. Cell Cycle. 2:202-210; Ganem, N.J., Z. Storchova, and D. Pellman. 2007. Curr. Opin. Genet. Dev. 17:157-162). However, there is little direct evidence linking cancer-causing mutations with such events, and it remains controversial whether genomic instability is a cause or an effect of cancer. In this study, we show that adenomatous polyposis coli (APC) mutations found in human colorectal cancers dominantly inhibit cytokinesis by preventing mitotic spindle anchoring at the anaphase cortex and, thus, blocking initiation of the cytokinetic furrow. We find that dividing crypt cells in the small intestines of APC(Min/+) mice exhibit similar mitotic defects, including misoriented spindles and misaligned chromosomes. These defects are observed in normal crypt cells with wild-type levels of beta-catenin and, importantly, are associated with tetraploid genotypes. We provide direct evidence that the dominant activity of APC mutants induces aneuploidy in vivo. Our data support a model whereby tetraploid cells represent a first step in the onset of genomic instability and colorectal cancer.

SUBMITTER: Caldwell CM

PROVIDER: S-EPMC2064647 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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APC mutations lead to cytokinetic failures in vitro and tetraploid genotypes in Min mice.

Caldwell Christine M CM Green Rebecca A RA Kaplan Kenneth B KB

The Journal of cell biology 20070901 7

Previous research has proposed that genomic instability contributes to cancer progression, with its initiation linked to tetraploid cell formation (Duesberg, P., and R. Li. 2003. Cell Cycle. 2:202-210; Ganem, N.J., Z. Storchova, and D. Pellman. 2007. Curr. Opin. Genet. Dev. 17:157-162). However, there is little direct evidence linking cancer-causing mutations with such events, and it remains controversial whether genomic instability is a cause or an effect of cancer. In this study, we show that ...[more]

PMID: 17893240

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Project description:Aberrant DNA methylation is frequently observed in colorectal cancer (CRC), but the underlying mechanisms and pathological consequences are poorly understood. Ten-Eleven Translocation (TET) dioxygenases and Thymine DNA Glycosylase (TDG) are involved in active DNA demethylation by generating and removing novel oxidized cytosine species. TET1 and TDG mutations, and alterations of the levels of oxidized cytosines have been identified in human CRC. To clarify the biological significance of the TET-TDG demethylation axis in intestinal tumorigenesis, we generated ApcMin mice that are devoid of Tet1 and/or Tdg, and characterized the methylome and transcriptome of intestinal adenomas by DREAM and RNA sequencing, respectively. Tet1-deficient and Tet1/Tdg-double heterozygous ApcMin adenomas manifested increased adenoma size and features of erosion or invasion, whereas an increased number (>30) of adenomas was found in Tdg-mutant ApcMin mice. Methylome analysis revealed progressive loss of global DNA hypomethylation in colonic adenomas from Tet1- and Tdg-deficient ApcMin mice, and hypermethylation of CpG islands in Tet1-deficient ApcMin mice. In addition, RNA sequencing showed upregulation of genes in inflammatory, immune and interferon response in Tet1- and Tdg-mutant colonic adenomas compared to control ApcMin adenomas. The corresponding 135-gene inflammatory signature separated human colonic adenocarcinomas into four groups, closely aligned with their microsatellite or chromosomal instability profile, and characterized by different levels of DNA methylation and DNMT1 expression levels that anti-correlated with TET1 expression levels. These findings demonstrate a novel mechanism of epigenetic regulation during intestinal tumorigenesis by which TET1-TDG-mediated active DNA demethylation decreases not only methylation levels, but also inflammatory/interferon/immune response, which impinges on the intrinsic features of genomic instability of the tumors. This study establishes a novel link, via inflammatory response, between epigenomic and genomic instability.

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APC mutations lead to cytokinetic failures in vitro and tetraploid genotypes in Min mice.

Publications

APC mutations lead to cytokinetic failures in vitro and tetraploid genotypes in Min mice.

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