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).

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Voiceover: So what makes a cell that's located inside of your nose responsible for smelling, say, a slice of pizza look and act differently from a cell that lines your gut and is responsible for absorbing the nutrients from that pizza? They have the exact same DNA so the differences can't be attributed to that fact alone. The answer actually lies in the expression of that DNA, which genes are actively transcribed and which ones aren't and there are several ways in which gene regulation occurs at the level of transcription and so we're going to be talking about the main ones here. Now let's draw out a hypothetical gene here and associated with this gene is a sequence upstream so towards the three prime region of the antisense strand, also called the template strand. And this sequence is called the promoter and there is another sequence in between the promoter and the gene called the operator. The operator is the sequence of DNA to which a transcription factor protein combined and the promoter is the sequence of DNA to which the RNA polymerase binds to start transcription. Now first off in prokaryotes we have what are called general transcription factors, which are a class of proteins that bind to specific sites on DNA to activate transcription. General transcription factors plus RNA polymerase and another protein complex called the mediator multiple protein complex constitute the basic transcriptional apparatus, which positions RNA polymerase right at the start of a protein coding sequence or a gene and then releases the polymerase to transcribe the messenger RNA from that DNA template. Now there's another type of DNA binding protein called activators and these enhance the interaction between RNA polymerase and a particular promoter, encouraging the expression of the gene and activators can do this by increasing the attraction of RNA polymerase for the promoter through interactions with sub units of the RNA polymerase or indirectly by changing the structure of the DNA. An example of an activator is the catabolite activator protein or CAP and this protein activates transcription of the lac operon in E. coli. In the case of the lac operaon and E. coli, cyclic adenosine monophosphate or cAMP is produced during glucose starvation and so this cAMP actually binds to the catabolite activator protein or CAP which causes a confirmational change that allows the CAP protein to bind to a DNA site located adjacent to the promoter and then this activator, the CAP, then makes a direct protein to protein interaction with RNA polymerase that recruits the RNA polymerase to the promoter. Now enhancers are sites on the DNA that are bound to by activators in order to loop the DNA in a certain way that brings a specific promoter to the initiation complex and as the name implies this enhances transcription of the genes in a particular gene cluster. And while enhancers are usually what are called cis-acting, cis meaning the same or acting on the same chromosome, an enhancer doesn't necessarily need to be particularly close to the gene that it acts on and sometimes it's not even located on the same chromosome. Enhancers don't act on the promoter region itself, but are actually bound by activator proteins and these activator proteins can interact with that mediator complex I mentioned earlier which recruits RNA polymerase and the general transcription factors which then can lead to transcription of the genes. So here I've drawn a little schematic of what it might look like to have the enhancer actually change the structure of the DNA so that the DNA is now looping around. Here you still have your promoter sequence, the operator sequence, the gene sequence, and the enhancer sequence, and having the DNA looped in such a way so that you could then recruit RNA polymerase, the transcription factors, the mediator protein complex, and then you have transcription begin of this gene here. Now let's talk about repressors. Repressors are proteins that bind to the operator, impending RNA polymerase progress on the strand and thus impeding the expression of the gene. Now if an inducer, which is a molecule that initiates gene expression, is present, then it can actually interact with the repressor protein in such a way that causes it to detach from the operator and then this frees up RNA polymerase to then transcribe the gene further down on the DNA strand. One example of a repressor protein is the repressor protein associated again with the lac operon operator, which prevents the transcription of genes used in lactose metabolism unless lactose, which is the inducer molecule, is present as an alternative energy source. Now silencers are regions of DNA that are bound by repressor proteins in order to silence gene expression and this mechanism is very similar to that of the enhancer sequences that I just talked about. And similarly, silencers can be located several bases upstream or downstream from the actual promoter of the gene and when a repressor protein binds to the silencer region of the DNA, RNA polymerase is prevented from binding to the promoter region. Now a few notes about the differences between prokaryotes and eukaryotes when it comes to transcriptional regulation. In prokaryotes, the regulation of transcription is really needed for the cell to be able to quickly adapt to the ever-changing outer environment that it is sitting in. The presence, the quantity, the type of nutrients actually determines which genes are expressed and in order to do that, genes must be regulated in some sort of fashion so a combination of activators, repressors, and rarely enhancers, at least in the case of prokaryotes, determines whether a gene is transcribed. In eukaryotes, transcriptional regulation tends to involve a combination of interactions between several transcription factors which allows for a more sophisticated response to multiple conditions in the environment. And another major difference between eukaryotes and prokaryotes is the fact that eukaryotes have a nuclear envelope which prevents the simultaneous transcription and translation of a particular gene and this adds an extra spacial and temporal control of gene expression.

CpG islands in promoters

In humans, about 70% of promoters located near the transcription start site of a gene (proximal promoters) contain a CpG island.^[1]^[2] CpG islands are generally 200 to 2000 base pairs long, have a C:G base pair content >50%, and have regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide and this occurs frequently in the linear sequence of bases along its 5′ → 3′ direction.^[3]^[4]

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 ERCC1, where the CpG island-containing promoter is located about 5,400 nucleotides upstream of the coding region of the ERCC1 gene.^[5] CpG islands also occur frequently in promoters for functional noncoding RNAs such as microRNAs.^[6]

Transcription silencing due to methylation of CpG islands

In humans, DNA methylation occurs at the 5′ position of the pyrimidine ring of the cytosine residues within CpG sites to form 5-methylcytosines. The presence of multiple methylated CpG sites in CpG islands of promoters causes stable inhibition (silencing) of genes.^[7] Silencing of transcription of a gene may be initiated by other mechanisms, but this is often followed by methylation of CpG sites in the promoter CpG island to cause the stable silencing of the gene.^[7]

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 gene set enrichment analysis, 569 out of 938 gene sets were hypermethylated and 369 were hypomethylated in cancers. Hypomethylation of CpG islands in promoters results in increased transcription of the genes or gene sets affected.^[11]

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 head and neck squamous cell carcinomas at least 15 DNA repair genes have frequently hypermethylated promoters; these genes are XRCC1, MLH3, PMS1, RAD51B, XRCC3, RAD54B, BRCA1, SHFM1, GEN1, FANCE, FAAP20, SPRTN, SETMAR, HUS1, and PER1.^[16] About seventeen types of cancer are frequently deficient in one or more DNA repair genes due to hypermethylation of their promoters.^[17] As summarized in one review article, promoter hypermethylation of the DNA repair gene MGMT occurs in 93% of bladder cancers, 88% of stomach cancers, 74% of thyroid cancers, 40%-90% of colorectal cancers and 50% of brain cancers.^{[citation needed]} Promoter hypermethylation of LIG4 occurs in 82% of colorectal cancers. This review article also indicates promoter hypermethylation of NEIL1 occurs in 62% of head and neck cancers and in 42% of non-small-cell lung cancers; promoter hypermetylation of ATM occurs in 47% of non-small-cell lung cancers; promoter hypermethylation of MLH1 occurs in 48% of squamous cell carcinomas; and promoter hypermethylation of FANCB occurs in 46% of head and neck cancers.^{[citation needed]}

On the other hand, the promoters of two genes, PARP1 and FEN1, were hypomethylated and these genes were over-expressed in numerous cancers. PARP1 and FEN1 are essential genes in the error-prone and mutagenic DNA repair pathway microhomology-mediated end joining. If this pathway is over-expressed, the excess mutations it causes can lead to cancer. PARP1 is over-expressed in tyrosine kinase-activated leukemias,^[18] in neuroblastoma,^[19] in testicular and other germ cell tumors,^[20] and in Ewing's sarcoma,^[21] FEN1 is over-expressed in the majority of cancers of the breast,^[22] prostate,^[23] stomach,^[24]^[25] neuroblastomas,^[26] pancreatic,^[27] and lung.^[28]

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]

References

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