Cancer Epigenetics From Mechanism to Therapy
Cell, Volume 150, Issue 1, 12-27, 6 July 2012
DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biological processes that are fundamental to the genesis of cancer.
Chromatin is the macromolecular complex of DNA and histone proteins, which provides the scaffold for the packaging of our entire genome. It contains the heritable material of eukaryotic cells. The basic functional unit of chromatin is the nucleosome. It contains 147 base pairs of DNA, which is wrapped around a histone octamer, with two each of histones H 2A , H2B, H3, and H4. In general and simple terms, chromatin can be subdivided into two major regions: (1) heterochromatin, which is highly condensed, late to replicate, and primarily contains inactive genes; and (2) euchromatin, which is relatively open and contains most of the active genes.
The term epigenetics was originally coined by Conrad Waddington to describe heritable changes in a cellular phenotype that were independent of alterations in the DNA sequence. Epigenetics is most commonly used to describe chromatin-based events that regulate DNA-templated processes.
The information conveyed by epigenetic modifications plays a critical role in the regulation of all DNA-based processes, such as transcription, DNA repair, and replication. Consequently, abnormal expression patterns or genomic alterations in chromatin regulators can have profound results and can lead to the induction and maintenance of various cancers.
DNA methylation is primarily noted within centromeres, telomeres, inactive X-chromosomes, and repeat sequences.
Although global hypomethylation is commonly observed in malignant cells, the best-studied epigenetic alterations in cancer are the methylation changes that occur within CpG islands, which are present in 70% of all mammalian promoters. CpG island methylation plays an important role in transcriptional regulation, and it is commonly altered during malignant transformation.
These have confirmed that between 5%10% of normally unmethylated CpG promoter islands become abnormally methylated in various cancer genomes. They also demonstrate that CpG hypermethylation of promoters not only affects the expression of protein coding genes but also the expression of various noncoding RNAs, some of which have a role in malignant transformation.
Understanding the cellular consequences of normal and aberrant DNA methylation remains a key area of interest, especially because hypomethylating agents are one of the few epigenetic therapies that have gained FDA approval for routine clinical use.
Although hypomethylating agents such as azacitidine and decitabine have shown mixed results in various solid malignancies, they have found a therapeutic niche in the myelodysplastic syndromes (MDS).
It is also emerging that the combinatorial use of DNMT and HDAC inhibitors may offer superior therapeutic outcomes.
early studies assessing the global distribution of this modification during embryogenesis had clearly identified an active global loss of DNA methylation in the early zygote, especially in the male pronucleus..
The N-acetylation of lysine residues is a major histone modification involved in transcription, chromatin structure, and DNA repair. Acetylation neutralizes lysine's positive charge and may consequently weaken the electrostatic interaction between histones and negatively charged DNA. For this reason, histone acetylation is often associated with a more open chromatin conformation..
Acetylation is highly dynamic and is regulated by the competing activities of two enzymatic families, the histone lysine acetyltransferases (KATs) and the histone deacetylases (HDACs). There are two major classes of KATs: (1) type-B, which are predominantly cytoplasmic and modify free histones, and (2) type-A, which are primarily nuclear and can be broadly classified into the GNAT, MYST, and CBP/p300 families.
HDACs are enzymes that reverse lysine acetylation and restore the positive charge on the side chain. There are 18 such enzymes identified, and these are subdivided into four major classes, depending on sequence homology. Class I (HDAC 1-3 and HDAC8) and class II (HDAC 4-7 and HDAC 9-10) represent the HDACs most closely related to yeast scRpd3 and scHda1, respectively, whereas class IV comprises only one enzyme, HDAC11. Class I, II, and IV HDACs share a related catalytic mechanism that requires a zinc metal ion but does not involve the use of a cofactor. In contrast, class III HDACs (sirtuin 17) are homologous to yeast scSir2 and employ a distinct catalytic mechanism that is NAD+-dependent. Analogous to the KATs, HDACs target both histone and nonhistone proteins.
Importantly, inhibitors of histone deactylases (HDAC-I) are able to reverse some of the aberrant gene repression seen in these malignancies and induce growth arrest, differentiation, and apoptosis in the malignant cells.
The best-characterized sites of histone methylation are those that occur on lysine residues and, therefore, these will be the focus of this section. Although many lysine residues on the various histones are methylated, the best studied are H3K4, H3K9, H3K27, H3K36, H3K79, and H4K20. Some of these (H3K4, H3K36, and H3K79) are often associated with active genes in euchromatin, whereas others (H3K9, H3K27, and H4K20) are associated with heterochromatic regions of the genome. monomethylation of H3K9 may be seen at active genes, trimethylation of H3K9 is associated with gene repression.
The phosphorylation of serine, threonine, and tyrosine residues has been documented on all core and most variant histones. Phosphorylation alters the charge of the protein, affecting its ionic properties and influencing the overall structure and function of the local chromatin environment. The phosphorylation of histones is integral to essential cellular processes such as mitosis, apoptosis, DNA repair, replication, and transcription. Generally speaking, the specific histone phosphorylation sites on core histones can be divided into two broad categories: (1) those involved in transcription regulation, and (2) those involved in chromatin condensation. Notably, several of these histone modifications, such as H3S10, are associated with both categories.
The high-throughput genomic platforms have established that virtually the entire genome is transcribed; however, only 2% of this is subsequently translated.
The remaining noncoding RNAs (ncRNAs) can be roughly categorized into small (under 200 nucleotides) and large ncRNAs. These RNAs are increasingly recognized to be vital for normal development and may be compromised in diseases such as cancer. The small ncRNAs include small nucleolar RNAs (snoRNAs), PIWI-interacting RNAs (piRNAs), small interfering RNAs (siRNAs), and microRNAs (miRNAs). Many of these families show a high degree of sequence conservation across species and are involved in transcriptional and posttranscriptional gene silencing through specific base pairing with their targets. In contrast, the long ncRNAs (lncRNAs) demonstrate poor cross-species sequence conservation, and their mechanism of action in transcriptional regulation is more varied. Notably, these lncRNAs appear to have a critical function at chromatin, where they may act as molecular chaperones or scaffolds for various chromatin regulators, and their function may be subverted in cancer
The principal tenet in oncologythat cancer is a disease initiated and driven by genetic anomaliesremains uncontested, but it is now clear that epigenetic pathways also play a significant role in oncogenesis.
In fact, it is now irrefutable that many of the hallmarks of cancer, such as malignant self-renewal, differentiation blockade, evasion of cell death, and tissue invasiveness are profoundly influenced by changes in the epigenome.
epigenetic regulators are targeted to these essential genes and what makes these genes solely reliant on certain epigenetic regulators..
hematopoietic malignancies are clearly more vulnerable to epigenetic interventions than solid malignancies. Thus, not all cancers are equally susceptible to epigenetic therapies..
It is likely that many of these new epigenetic drugs offer synergistic benefits, and these new therapies may also synergize with conventional chemotherapies. This strategy of combination therapy may not only increase therapeutic efficacy but also reduce the likelihood of drug resistance.
The plethora of genetic lesions in epigenetic regulators offers many possible targets for drug discovery and will no doubt attract the attention of the pharmaceutical industry.
Cell, Volume 150, Issue 1, 12-27, 6 July 2012
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