Regulation of transcription in cancer
Generally, in progression to cancer, hundreds of genes are silenced or activated. Although silencing of some genes in cancers occurs by mutation, a large proportion of carcinogenic gene silencing is a result of altered DNA methylation (see DNA methylation in cancer). DNA methylation causing silencing in cancer typically occurs at multiple CpG sites in the CpG islands that are present in the promoters of protein coding genes.
Altered expressions of microRNAs also silence or activate many genes in progression to cancer (see microRNAs in cancer). Altered microRNA expression occurs through hyper/hypo-methylation of CpG sites in CpG islands in promoters controlling transcription of the microRNAs.
Silencing of DNA repair genes through methylation of CpG islands in their promoters appears to be especially important in progression to cancer (see methylation of DNA repair genes in cancer).
CpG islands in promoters
In humans, about 70% of
Genes may also have distant promoters (distal promoters) and these frequently contain CpG islands as well. An example is the promoter of the DNA repair gene
Transcription silencing due to methylation of CpG islands
In humans,
Transcription silencing/activation in cancers
In cancers, loss of expression of genes occurs about 10 times more frequently by transcription silencing (caused by promoter hypermethylation of CpG islands) than by mutations. As Vogelstein et al. point out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations.[8] In contrast, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa.[9][10][11]
Using
One study[12] listed 147 specific genes with colon cancer-associated hypermethylated promoters and 27 with hypomethylated promoters, along with the frequency with which these hyper/hypo-methylations were found in colon cancers. At least 10 of those genes had hypermethylated promoters in nearly 100% of colon cancers. They also indicated 11 microRNAs whose promoters were hypermethylated in colon cancers at frequencies between 50% and 100% of cancers. MicroRNAs (miRNAs) are small endogenous RNAs that pair with sequences in messenger RNAs to direct post-transcriptional repression. On average, each microRNA represses or inhibits transcriptional expression of several hundred target genes. Thus microRNAs with hypermethylated promoters may be allowing enhanced transcription of hundreds to thousands of genes in a cancer.[13]
Transcription inhibition and activation by nuclear microRNAs
For more than 20 years, microRNAs have been known to act in the cytoplasm to degrade transcriptional expression of specific target gene messenger RNAs (see microRNA history). However, recently, Gagnon et al.[14] showed that as many as 75% of microRNAs may be shuttled back into the nucleus of cells. Some nuclear microRNAs have been shown to mediate transcriptional gene activation or transcriptional gene inhibition.[15]
DNA repair genes with hyper/hypo-methylated promoters in cancers
DNA repair genes are frequently repressed in cancers due to hypermethylation of CpG islands within their promoters. In
On the other hand, the promoters of two genes,
DNA damage appears to be the primary underlying cause of cancer.[29][30] If accurate DNA repair is deficient, DNA damages tend to accumulate. Such excess DNA damage can increase mutational errors during DNA replication due to error-prone translesion synthesis. Excess DNA damage can also increase epigenetic alterations due to errors during DNA repair. Such mutations and epigenetic alterations can give rise to cancer (see malignant neoplasms). Thus, CpG island hyper/hypo-methylation in the promoters of DNA repair genes are likely central to progression to cancer.[31][32]
See also
References
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