Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis

Yasuhiro Yamada, Laurie Jackson-Grusby, Heinz Linhart, Alex Meissner, Amir Eden, Haijiang Lin, Rudolf Jaenisch*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

221 Scopus citations


Genome-wide DNA hypomethylation and concomitant promoter-specific tumor suppressor gene hypermethylation are among the most common molecular alterations in human neoplasia. Consistent with the notion that both promoter hypermethylation and genome-wide hypomethylation are functionally important in tumorigenesis, genetic and/or pharmacologic reduction of DNA methylation levels results in suppression or promotion of tumor incidence, respectively, depending on the tumor cell type. For instance, DNA hypomethylation promotes tumors that rely predominantly on loss of heterozygosity (LOH) or chromosomal instability mechanisms, whereas loss of DNA methylation suppresses tu mors that rely on epigenetic silencing. Mutational and epigenetic silencing events in Wnt pathway genes have been identified in human colon tumors. We used ApMin/+ mice to investigate the effect of hypomethylation on intestinal and liver tumor formation. Intestinal carcinogenesis in ApMin/+ mice occurs in two stages, with the formation of microadenomas leading to the development of macroscopic polyps. Using Dnmt1 hypomorphic alleles to reduce genomic methylation, we observed elevated incidence of microadenomas that were associated with LOH at Apc. In contrast, the incidence and growth of macroscopic intestinal tumors in the same animals was strongly suppressed. In contrast to the overall inhibition of intestinal tumorigenesis in hypomethylated Apc Min/+ mice, hypomethylation caused development of multifocal liver tumors accompanied by Apc LOH. These findings support the notion of a dual role for DNA hypomethylation in suppressing later stages of intestinal tumorigenesis, but promoting early lesions in the colon and liver through an LOH mechanism.

Original languageAmerican English
Pages (from-to)13580-13585
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number38
StatePublished - 20 Sep 2005


  • APC
  • Dnmt1 intestinal cancer
  • Liver cancer
  • Loss of heterozygosity


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