Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis

Abstract

Genome-wide DNA hypomethylation and concomitant promoterspecific 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 and͞or 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 tumors that rely on epigenetic silencing. Mutational and epigenetic silencing events in Wnt pathway genes have been identified in human colon tumors. We used Apc Min/؉ mice to investigate the effect of hypomethylation on intestinal and liver tumor formation. Intestinal carcinogenesis in Apc Min/؉ 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.APC ͉ Dnmt1 ͉ intestinal cancer ͉ liver cancer ͉ loss of heterozygosity C hanges in the DNA methylation status are among the most common molecular alterations in human neoplasia (1). Although genome-wide DNA hypomethylation was observed in a wide variety of human cancers Ͼ20 years ago (2-4), the functional significance of this alteration is still unclear. In colon carcinogenesis, DNA hypomethylation has been observed in both adenomas and adenocarcinomas (4), suggesting that it is associated with early stages of carcinogenesis. However, similar early-stage lesions also display gene silencing through promoter hypermethylation (1). Ninety percent of colorectal cancers display Wnt pathway activation through either mutation or epigenetic silencing of genes in the canonical Wnt signaling pathway (5). Apc Min/ϩ mice have a mutation in the canonical Wnt pathway and are predisposed to form intestinal tumors (6). In Apc Min/ϩ mice, tumors arise as a result of loss of heterozygosity (LOH) at Apc as well as through LOH-independent mechanisms (7).Several experiments have demonstrated that global DNA hypomethylation induced by hypomorphic Dnmt1 alleles significantly suppresses intestinal tumorigenesis in Apc Min/ϩ mice (8-10). In contrast, global DNA hypomethylation promotes chromosomal instability in ES cells (11) and mic...

Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors)

“…The DNA methyltransferase-1 hypomorphic mice had suppression of polyp formation and reduction in the frequency of CpG island methylation in both the normal mucosa and adenomas in Apc (Min/ þ ) mice, but developed T-cell lymphomas and liver tumors. [30][31][32] In our current study, LINE-1 relative tumor hypomethylation was more common in patients whose tumors had loss of chromosome 18 and methylation of RASSF1A, gene but was inversely correlated with MGMT gene methylation. However, in our study, hypomethylation is not a sensitive or valuable marker of generalized CpG island methylation status (methylation of multiple genes).…”

Epigenetics provides a new generation of oncogenes and tumour-suppressor genes

“…Results obtained in mouse models again reflect the need for well-adjusted DNMT function to maintain cellular homeostasis: DNMT1 knockout mice are 'protected' against the development of colorectal adenomas when crossed with APC-deficient mice (Laird et al, 1995), but they are 'prone' to develop lymphomas in the context of mice susceptible to this type of neoplasia (Eden et al, 2003). These latter results may be explained if lymphomas rely predominantly on chromosomal instability dependent on genomic DNA hypomethylation, while colon tumours rely more on the CpG island methylation status of tumour-suppressor genes (Yamada et al, 2005).…”

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

“…Additional studies of the doubly targeted cells suggest that at least some histone modifications occur before alterations in DNA methylation (Bachman et al, 2003). Mice expressing a hypomorphic Dnmt1 protein develop T-cell lymphomas , and when this deficiency is crossed into other tumor models, tumor incidence increases Yamada et al, 2005). Dnmt3b deficiency inhibits the formation of macroadenomas in the murine Apc Min/ þ colon cancer model, indicating a requirement for Dnmt3b activity in the transition from microadenoma to tumor (Lin et al, 2006).…”