A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer

Abstract

Aberrant hypermethylation of gene promoters is a major mechanism associated with inactivation of tumor-suppressor genes in cancer. We previously showed this transcriptional silencing to be mediated by both methylation and histone deacetylase activity, with methylation being dominant. Here, we have used cDNA microarray analysis to screen for genes that are epigenetically silenced in human colorectal cancer. By screening over 10,000 genes, we show that our approach can identify a substantial number of genes with promoter hypermethylation in a given cancer; these are distinct from genes with unmethylated promoters, for which increased expression is produced by histone deacetylase inhibition alone. Many of the hypermethylated genes we identified have high potential for roles in tumorigenesis by virtue of their predicted function and chromosome position. We also identified a group of genes that are preferentially hypermethylated in colorectal cancer and gastric cancer. One of these genes, SFRP1, belongs to a gene family; we show that hypermethylation of four genes in this family occurs very frequently in colorectal cancer, providing for (i) a unique potential mechanism for loss of tumor-suppressor gene function and (ii) construction of a molecular marker panel that could detect virtually all colorectal cancer.

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines

“…In addition, one ovarian cancer cell line, TOV112D, and one colorectal cancer cell line, DLD-1, did not express TCF2, although little or no methylation was detected in tumours. Genes silenced in cancer are often not expressed in cancer cell lines (Suzuki et al, 2002), and their silencing may be caused by mechanisms other than methylation, for example by the absence of a transcription factor or histone modification (Kondo et al, 2004).…”

Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders

“…Although this method has an apparent disadvantage of the difficulty of excluding false positives caused by secondary effect of drug treatment, this method has been successfully applied to the identification of hypermethylated CpG islands in cancer cells. 86 We checked the DNA methylation status of the candidate genes that upregulated after the 5-aza-dC treatment only in one of the twins, and found the differences in methylation status between MZ twins, although their pathophysiological significances remain elusive (Iwamoto et al, in preparation).…”

Antibody response to a non‐conserved C‐terminal part of human histone deacetylase 3 in colon cancer patients

“…23,24 Confirmation of HDAC role in gene regulation in human colorectal cancer was provided recently by a study in which inhibition of histone deacetylases (with or without demethylation of DNA) led to increased expression of substantial number of genes that are epigenetically silenced in this type of malignancy. 5 Despite significant similarities to other Class I HDAC (especially to HDAC1 and HDAC2), HDAC3 possesses several unique features. In particular, HDAC3 can be found in the nucleus and in the cytoplasm, whereas all other Class I HDAC are strictly nuclear proteins.…”

“…1,2 Histone deacetylases (HDAC) represent the family of enzymes involved in dynamic regulation of chromatin structure during transcription, but can also deacetylate a number of non-histone substrates. [3][4][5][6][7][8][9] A growing body of evidence implicates HDAC as playing an important role in carcinogenesis, particularly, in colorectal cancer, as suggested by expression profiling of colon cancer cells treated by HDAC inhibitor trichostatin A. [3][4][5] Histone deacetylases may be involved in carcinogenesis in different ways.…”