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Tulane Medical School, New Orleans, LA 70112
3To whom correspondence should be addressed. .
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONLITERATURE CITED |
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KEY WORDS: • DNA methylation • cancer • hypomethylation • hypermethylation • ICF
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONLITERATURE CITED |
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,2
) and by our laboratory (3
). The type of abnormality found in these studies was cancer-associated hypomethylation and preceded reports of DNA hypermethylation in human cancers by 3 y. In animal models for carcinogenesis, both hypomethylation and hypermethylation were reported even earlier (4
,5
). Cancer-linked DNA hypomethylation probably is just as prevalent as cancer-associated DNA hypermethylation.
Although far more attention recently has been paid to the important and pervasive role that de novo methylation of the promoter regions of tumor suppressor genes plays in oncogenesis (6
), much evidence indicates that abnormal DNA hypomethylation also contributes to oncogenic transformation or tumor progression. Experiments with the DNA demethylating agents 5-azadeoxycytidine or 5-azacytidine support a cause-and-effect relationship between this hypomethylation and carcinogenesis. These include conversion of low-metastatic cell lines to high-metastatic cells (7
,8
) and formation of transformed foci (9
) or tumorigenic cell lines in association with a rearrangement in the vicinity of the centromere of chromosome 3 (10
) upon such treatment. At noncytotoxic doses, 5-azacytidine caused a baby hamster kidney-derived cell line to undergo a high frequency of cellular transformation with no detectable mutagenesis (11
). 5-Azadeoxycytidine and 5-azacytidine caused thyroid adenomas in goitrogen-treated mice (12
). Although these drugs are used in the treatment of certain leukemias (13
), their chemotherapeutic effects probably are due in part to their toxicity at high doses via their inhibition of DNA replication rather than to DNA demethylation (14
). Feeding rats and mice methyl-deficient diets resulted in hepatocarcinogenesis, global DNA undermethylation and protooncogene demethylation, although diet effects other than DNA hypomethylation could contribute to tumor formation (15
–20
). Insertional inactivation of the DNA methyltransferase 1 (Dnmt1) gene in a heterozygous knockout transgenic mouse induced thymic lymphomas, especially in combination with low levels of 5-azadeoxycytidine, which had no effect in normal mice (L. Jackson-Grusby and R. Jaenisch, cited in Ref. 21
). The same research group also showed that decreased methylation increased benign polyp formation in a mouse model for familiar adenomatous polyposis (Min mice) (22
). The effects of altering DNA methylation levels on tumorigenesis apparently depend on the model system used and the exact method of treatment. This probably is because a variety of types of aberrations in DNA methylation can contribute to oncogenic transformation.
We have been studying the immunodeficiency, centromeric region instability, facial anomalies (ICF4
) syndrome to gain insight into the relationship between DNA hypomethylation and cancer. This unique recessive disease is caused by diverse mutations in one of the three known genes encoding human DNA methyltransferases (DNMT3B). These mutations often are missense mutations in the portion of the gene specifying the catalytic domain (23
). As described below, various types of cancer (24
–26
) share with ICF syndrome cells the property of being hypomethylated in satellite 2 DNA (Sat2), the predominant DNA sequence of the centromere-adjacent (juxtacentromeric) heterochromatin of chromosome (Chr)1 and Chr16 (Fig. 1
). Normal somatic tissues are highly methylated in these regions, just as other constitutive heterochromatin regions are in vertebrates (24
–26
). Only Chr1 and Chr16 contain these long regions of Sat2-rich chromatin adjacent to the centromeric heterochromatin, and only these regions are targeted for high frequencies of chromatin decondensation and rearrangements in the vicinity of their centromeres (pericentromeric rearrangements; Fig. 1
) in mitogen-stimulated ICF lymphocytes and ICF lymphoblastoid cell lines (LCLs) (27
,28
).
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONLITERATURE CITED |
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Methods for high-performance liquid chromatography (HPLC) analysis on enzymatic digests of DNA were as previously described (3
,28
,29
). Recently, we have been heat denaturing and quick cooling the DNA prior to nuclease P1 treatment instead of using a deoxyribonuclease I digestion step. The analysis of the 5-methylcytosine (5-MC) content at the deoxynucleoside level precludes artifacts due to large amounts of residual RNA degradation products (ribooligonucleotides formed during RNase digestion) that sometimes are present and undetected in DNA samples. Also for that reason, DNA samples generally were spooled after ethanol precipitation rather than pelleted.
Southern blot analysis
DNA methylation analysis of Sat2 DNA was via Southern blotting of DNA digested with the cytosine guanine (CpG) methylation-sensitive restriction endonuclease BstBI with an internal control for complete digestion as previously described (24
–26
,28
).
Karyotype analysis
Karyotype analysis was performed on G-banded metaphase chromosomes by standard techniques (28
).
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONLITERATURE CITED |
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By HPLC analysis of DNA digested enzymatically to deoxymononucleosides, in collaboration with C. Gehrke (University of Missouri, Columbia, MO) we determined the 5-MC content of various normal tissue DNAs and compared these to DNA from a wide variety of human cancers (3
,29
). These results are summarized in Table 1
. The 5-MC contents originally were expressed as the percentage of the bases as 5-MC and are shown in Table 1
as the percentage of DNA cytosine (C) residues methylated using the 5-MC plus C content of normal human tissue DNAs (21 mol%) (3
,29
). By comparing a variety of cancers to a variety of postnatal somatic tissues, problems of uncertainties about the genomic 5-MC content of the cell type of origin of the cancer were avoided. However, the results obtained probably are an underestimate of the extent of hypomethylation of the DNA of the cancer because cancers often are interspersed with considerable amounts of normal tissues and the cancer samples used in this study had not been microdissected. In collaboration with A. Feinberg (Johns Hopkins University, Baltimore, MD) and C. Gehrke, we also showed that colon adenocarcinomas had an average 10% deficiency in their DNA 5-MC content compared to adjacent normal mucosa, the tissue of origin of these cancers (30
). However, in that study almost as much genomic hypomethylation was seen in the DNA of colon polyps compared to normal mucosa, while in the previous study of other types of benign tumors, DNA hypomethylation was not apparent in comparison to a variety of normal postnatal somatic tissues (3
). It is likely that only some types of benign tumors display global DNA hypomethylation.
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). As often seen in cultured human cells, there was global DNA hypomethylation of all the examined LCLs relative to normal postnatal somatic tissue DNAs. The ICF LCLs did not have a lower overall level of 5-MC in their DNA than the LCLs from the phenotypically normal parents of an ICF patient [
3.1 mol% 5-MC/(5-MC + C)]. A comparison of the genomic 5-MC levels in uncultured ICF tissue is even more informative because no in vitro cultivation was involved. The ICF brain sample showed a decrease in the genomic 5-MC levels of 7% compared to normal brain samples, including one from an infant. This is a relatively modest decrease compared to some of the naturally occurring tissue-specific differences in human genomic methylation levels in normal and cancerous tissues (Table 1)
. DNA hypomethylation in cancer and the ICF syndrome: satellite DNA hypomethylation
All examined ICF tissue and cell populations are hypomethylated in the major component of 1qh and 16qh, namely Sat2, in contrast to normal postnatal somatic tissues, which are highly methylated in this DNA repeat (27
,28
). That hypomethylation is targeted to this region is seen in our finding that the extent of hypomethylation of this satellite DNA is much greater than the extent of global DNA hypomethylation in ICF. We have shown that Sat2 in both Chr1 and Chr16 also is hypomethylated in a large fraction of three diverse kinds of cancer that we examined: ovarian epithelial carcinomas, breast adenocarcinomas and Wilms tumors (24
–26
). Hypomethylation of centromeric satellite 
DNA of Chr1 is atypical in ICF but frequent in Wilms tumors and ovarian epithelial carcinomas (25
,26
,28
,31
). Recently, we have shown that satellite DNA examined for DNA methylation under conditions of low-stringency hybridization can be extensively hypomethylated throughout the genome in Wilms tumors and ovarian epithelial carcinomas (our unpublished results).
By loss of heterozygosity analysis, we found a significant relationship between the loss of 16q and hypomethylation of 16qh Sat2 DNA in Wilms tumors (26
). We are testing the hypothesis that hypomethylation contributes to pericentromeric rearrangements in Chr1 and Chr16 by simultaneous cytogenetic and DNA methylation analyses on these tumors. In our study of ovarian epithelial tumors in collaboration with L. Dubeau (University of Southern California, Los Angeles, CA), we compared Sat2 hypomethylation to genomic levels of 5-MC, which Dubeau et al. (32
) had previously determined. There was a statistically significant association (P < 0.005) between genome-wide hypomethylation and undermethylation of Sat2 DNA in the ovarian tumors. In that study, we examined Sat2 DNA methylation in ovarian tumors of different malignant potential, namely ovarian cystadenomas, low malignant potential tumors and epithelial carcinomas. A comparison of methylation of these sequences in the three types of ovarian neoplasms demonstrated that there also was a statistically significant correlation between the extent of this satellite DNA hypomethylation and the degree of malignancy (P < 0.01). We propose that one of the reasons that global DNA hypomethylation so often is seen in cancers is that it often includes hypomethylation of repeated DNA sequences, which aids in oncogenic transformation or tumor progression. In this regard it is interesting to note that most of the hypomethylated sequences in ICF appear to be DNA repeats, including repeats not located in the pericentromeric regions but frequently hypomethylated in some types of cancers (33
).
Functional significance of satellite DNA hypomethylation in cancer and the ICF syndrome
Not only is there an association between Sat2 DNA hypomethylation and rearrangements in its vicinity (pericentromeric Chr1 and, usually to a lesser extent, Chr16 rearrangements) but also we have shown that treatment of a normal pro-B cell line with the DNA demethylating agents 5-azadeoxycytidine or 5-azacytidine induces the same spectrum and high frequency of Chr1 rearrangements characteristic of ICF LCLs or mitogen-treated lymphocytes from ICF patients (34
,35
). Other DNA-damaging agents tested did not display any specificity for these regions (34
–36
). The extraordinary collection of chromosomal anomalies specifically seen in the pericentromeric regions in these normal cells treated with DNA demethylating agents and in ICF LCLs or mitogen-stimulated lymphocytes include decondensation of 1qh and 16qh, multiradial chromosomes with 3–12 Chr1 and/or Chr16 arms joined in the pericentromeric region and whole-arm deletions. These Chr1 and Chr16 anomalies were seen in up to 60% of the untreated cells from ICF LCLs (28
) and in 20–40% of the 5-azadeoxycytidine– or 5-azacytidine–treated normal pro-B cells (34
,35
). No other consistent chromosomal abnormality was seen in the ICF LCLs or the demethylating agent-treated normal pro-B cell line except for various telomeric associations in the ICF LCLs. Surprisingly, multiradials composed of arms of both Chr1 and Chr16 were favored over homologous associations and cells containing multiradials with three or more than four arms almost always displayed losses or gains of Chr1 or Chr16 arms from the metaphase (Table 2
). Our results suggest that decondensation of 1qh and 16qh often leads to unresolved Holliday junctions, chromosome breakage, arm missegregation and the formation of multiradials that may yield more stable chromosomal abnormalities (28
) (Fig. 2
). The ICF LCLs retain the ICF-specific pattern not only of chromosomal rearrangements but also of targeted DNA hypomethylation (28
). This hypomethylation of heterochromatic DNA sequences, which is seen in many cancers, as described above, may predispose to chromosome rearrangements in cancer as well as in ICF.
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). However, only 10–25% of Chr1 homologues were decondensed in 1qh in these cells. Therefore, undermethylation does not necessarily cause the loss of heterochromatin structure, but it apparently predisposes to it. A major function of the high level of methylation at 1qh and 16qh may be to minimize a heterochromatin-to-euchromatin transition that might otherwise occasionally occur.
Based on our detailed analysis of the karyotypes of the ICF LCLs, we proposed a model for the origin of multiradial chromosomes in ICF lymphoid cells (Fig. 2)
. In this model, the multiradial chromosomes are only very short-lived intermediates that can resolve upon cell division to yield more stable pericentromeric rearrangements of the sort overrepresented in many kinds of cancers [e.g., whole-arm deletions, isochromosomes (chromosomes with two short or two long arms joined in the pericentromeric region instead of one short and one long arm) and pericentromeric translocations between Chr1 and Chr16]. The hypomethylation of the 1qh and 16qh regions may predispose to decondensation of normally constitutive heterochromatin, which in turn could increase local recombination involving homologous or partially homologous satellite DNA repeats. This has been proposed for multiple myeloma on the basis of cytogenetic analyses of bone marrow cells revealing ICF-like chromosomal abnormalities (37
).
Last, our recent microarray gene expression study of ICF versus normal LCLs (38
) suggests that abnormal hypomethylation of constitutive heterochromatin may affect expression of genes elsewhere in the genome by indirect effects. These effects could be repressive heterochromatin-euchromatin interactions bridged by specific DNA-binding proteins as has been hypothesized for centromeric heterochromatin and early lymphoid-specific genes recognized by the Ikaros transcription control protein (39
). Alternatively, constitutive heterochromatin can serve as a reservoir for transcription control proteins, and its binding of these proteins could be influenced by its state of methylation. When abnormal amounts of these proteins are sequestered in these heterochromatic regions, dysregulation of genes under the control of these proteins could result. In either case, hypomethylation-associated abnormalities in juxtacentromeric and centromeric heterochromatin during oncogenesis or tumor progression could regulate expression of euchromatic genes in a manner that promotes cancer formation. Therefore, cancer-associated hypomethylation of satellite DNA sequences might function not only in increasing karyotypic instability but also in altering gene expression to favor carcinogenesis.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported in part by National Institutes of Health Grant CA81506.
4 Abbreviations used: Chr, chromosome; ICF, immunodeficiency, centromeric region instability, facial anomalies syndrome; LCL, lymphoblastoid cell line; Sat2, satellite 2 DNA; 1qh, the juxtacentromeric heterochromatin of chromosome 1; 16qh, the juxtacentromeric heterochromatin of chromosome 16; 5-MC, 5-methylcytosine.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONLITERATURE CITED |
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