The Role of Epigenetics in the Development and Progression of Cancer - Literature review Example

Discuss the evidence for the notion that epigenetics, rather than ical genetics, can account for the origin and progression of tumours Introduction Until almost a decade ago, researchers mainly thought that cancer occurred due to alterations in the patterns of DNA in certain genes. The increasing rates of cancer has made scientists extend their research to ascertain various changes in DNA of certain genes. The main intention of such a research has been to ascertain various mechanisms involved in the evolution and progress of each type of tumor and tumor variant. One of the major benefits of understanding the development of tumor is the possibility of early detection of cancer which is very crucial to institute appropriate treatment and thus improve prognosis. Such immense research has thrown light on the involvement of epigenetic mechanisms apart from genetic mechanisms in the development of tumors. Infact, recent research by many cancer scientists like Baylain and Herman (2000) has suggested the role of both genetic and epigenetic mechanisms in the development and progression of cancer. Epigenetic mechanisms involve changes in gene expression that are not only heritable but also occur without any alteration in the DNA sequences. Das and Singal (2004) have defined epigenetics as a stable alteration in gene expression potential that takes place during development and cell proliferation, without any change in gene sequence. Research in epigenetics hs proven the role of mainly 2 epigenetic mechanisms in the pathogenesis of cancer. They are DNA methylation and covalent modifcation of histones. It is interesting to know that both these mechanims are actually interconnected. The most common epigenetic event happening in the mamalian genome is DNA methylation (Das and Singal, 2004). There is another epigenetic mechanism that has some role in tumorigenesis and that is formation of repressive chromatin state by RNA. Scientists are of the opinion that these discoveries and advances in the field of epigenetics are only a beginning and there are probably several other mechanisms involved in the development of cancer and thus more research is warranted in this field. Epigenetics have a role not only in cancer biology but also in several fields like viral infections, cloning, somatic gene therapy, activity of mobile elemets, transgenic technologies, genomic imprinting and mental health (Das and Singal, 2004). In this essay, the role of epigenetics in the development and progression of cancer will be discussed through review of literature pertaining to th topic. Gene silencing through DNA hypermethylation and cancer Extensive research has led to the discovery of gene silencing and its role in cancer progression. Of the several genetic mechanisms associated with cancer development, DNA hypermethylation has been widely studied and associated with tumorigenesis. There is increased emphasis to delineate specific genes which have undergone this process to innovate novel genomic screening approches. Baylin, Esteller, Rountree, et al (2001) reviewed studied hypermethylated genes associated with human cancers and reported that half of the genes which cause familial forms of cancer in human beings are actually hypermethylated. Various screening methods for cancer with respect to genetic alterations, which are available as of now are not universal tumor markers and thus early detection becomes difficult (Esteller, Corn, Baylin et al, 2001). Research has shown that certain alterations like hypermethylation of certain parts of the gene the gene promoters, cause silencing of tumor suppression and this mechanism can be used for universal screening . Currently, further research is in progress to use gene silencing as a molecular marker for early detection of cancer. Of the several genetic mechanisms associated with cancer development, DNA hypermethylation has been widely studied and associated with tumorigenesis. There is increased emphasis to delineate specific genes which have undergone this process to innovate novel genomic screening approches. Baylin, Esteller, Rountree, et al (2001) reviewed studied hypermethylated genes associated with human cancers and reported that half of the genes which cause familial forms of cancer in human beings are actually hypermethylated (Refer to appendix). Such an aberrant hypermethylation can occur very early in the progression of tumor and can cause severe pathway abnormalities like cell cycle control loss, altered function of various transcription factors, disruption of cell to cell interaction, disruption of cell to substratum interaction, altered function of the receptors, signal transduction pathway inactivation, loss of signals pertaining to apoptosis and instability of the cell genetics (Baylin et al, 2001). Gene silencing is one of the mechanisms of gene regulation during which the expression of gene is either interrupted or suppressed at transcriptional or translational levels. For the past 30 years, researchers have been working on manual methods of gene silencing as a mode of treatment for some diseases. Current research has identified the role of gene silencing in the development of certain cancers, especially in non-familial types of colon cancer and renal cancer. This has interested the experts because unlike mutation, gene silencing is reversible; and theoretically it means that reversal of gene silencing should stop the progression of cancer (Esteller, Corn, Baylin et al, 2001). Thus identification of gene silencing of tumor progression genes in cancer has 2 purposes: 1. Molecular marker for early detection of cancer. 2. Possibility of treatment due to reversal of gene slicing. Extensive research in epigenetic mechanisms of cancer has led to several treatment methods targetted to reverse DNA methylation. Drugs like 5- azacytidine, histone deacetylase inhibitor and decitabine reverse DNA methylation and are used in the treatment of several tumors (Das and Singal, 2004). Newer antimethylation agents like small interference RNA and antisense DNA methyl transferase and under trial (Das and Singal, 2004). Mokarram, Kumar and Brim (2009) studied gene silencing of a set of genes known as Candidate Cancer Genes or CAN genes of colorectal cancer in 51 Iranians and 51 African-Americans. They found that in both the populations, more than 65% gene silencing in the form of hypermethylation was noted in certain genes and in another set of genes, gene silencing was less than 50%. The researchers also found that while 31% of the tumors in African -American population showed gene silencing in a particular group of genes, only 28% of Iranian genes demonstrated these changes. These differences have been attributed to the differences in cancer progression observed clinically in both the populations. Mokarram et al (2009) concluded that CAN genes are useful markers for colon carcinogenesis and that the differences in gene silencing was the reason for the higher incidence and aggression of colorectal cancer in African-American population. Martin-Subero et al (2009) studied gene silencing in 367 blood and lymphoid tissue- related cancers. In their study, the researchers found that gene silencing was more prominent and frequent in lymphoid malignancies than in myeloid malignancies. They also found a high correlation between the number of hypermethylated and hypomethylated genes in several mature B-cell neoplasias, but not in precursor B- and T-cell leukemias. The study concluded that silenced genes play a major role in the development of different types of blood cancers. Karray-Chouayekh, et al (2009) evaluated the gene silencing patterns of 2 genes which are related to colon cancer and breast cancer. The authors found that the frequencies of gene silencing in the former was 24.36% and that for the latter was 46%. In the same study, the researchers also deducted that gene silencing of a particular gene was highly correlated with a particular gene expression and overall survival. This proves the role of gene silencing as an useful indicator of poor prognosis of breast cancer. Hesson et al (2009) characterized the expression of a set of genes called RASSF10, whose family members have been known to be inactivated in several cancer types. The characterization was done in normal human bone marrow. The authors found that gene silencing of these genes is a distinct feature in childhood leukemias. Vladimirova et al (2009) studied characterization of LHX9 gene in patients with a type of brain tumor. They found that gene silencing of this gene occurred at two specific regions and was associated with reduced messenger RNA expression. Another interesting feature of this study is that the researchers were able to reverse gene silencing using a drug. Thus it is hoped that reversal of gene silencing can be a novel therapeutic approach to pediatric glioma. Histone modifications and cancer The histone part of N-terminal tails is crucial to maintain the stability of chromatin and is subject to many modifications. Many of these modifications have a role in the regulation of transcription, thus have cancerous potential when the deregulation deposition takes a lead (Bannister, 2009). The main histone modifications that have been incriminated in the development of cancer are aberrations in acetylation, methylation and phosphorylation. The acetylation of histones opens the chromatin structure. There are 2 types of enzymes which are involved in the process. The histone acetyltransferases or HATs are transcriptional activators and the histone deacetylases or HDACs are repressors. A classic example of mutation of HAT leading to cancer is the p300 HAT gene that has been incriminated in the pathophysiology of many gastrointestinal tumors (Bannister, 2009). While alterations in HAT genes have been linked to various forms of cancer, there is no evidence to prove that alterations in HDACs causes cancer. Infact, these enzymes rarely get mutated. There is however, some evidence to show that inhibition of HDACs causee regression of cancer (Bannister, 2009). Thus anti- HDAC agents are in use for cancer therapy. The lysine methyltransferases which target the histone part of the N-terminal tails contains SET domains. Absence of lysine methyltransferase activity due to aberration or mutation of the genes concerned to the enzymes results in upholding of SET domain proteins which have been implicated in cancer. One classical example of aberration of methylation changes induced cancer activity is the dysregulation of methylation of H3K9 due to absence of lysine methyl transferases that causes B cell lymphomas. Another major histone modification which has been incriminated in cancer is misregulation of phosphorylation of H3S10 and H3S28 which are crucial parts of cell cycle. This phosphorylation is performed by aurora kinases which have been implicated in cancers. Cang, Feng, Konno et al (2009) studied the acetylation status of histone H3 in cells of human prostate cancer. The study was conducted through assessment of multiple acetylation sites at N-termini. In this study, the authors found that in prostatic adenocarcinomas, deficient acetylation of histone H3 was detected which was classically absent in normal tissues. The adenocarcinomas and cancer cell lines exhibited deacetylation at particular status, especially at lysine points, pointing to the role of deacetylation in the development of cancer. One important finding in the study was significant elevation of HDACs in adenocarcinomas and cancer cell lines which is secondary to deficient histone acetylation. Kawamoto, Okino, Place et al (2007) analysed the methylation status of RASSF1A gene, histone acetylation and H3 methylation in the promotor regions of prostatic cancer cells and cell lines. The results of the study found that while levels of acetyl H3, acetyl H4 and dimethyl-H3-K4 were noticed to be enriched in the carcinoma cells and cell lines, depletion of H3K9me2 was seen. The authors concluded by implying a role of dysregulation of histone acetylation and methylation in the development of prostate cancer. Role of RNA in cancer development RNA is involved in chromatin regulation. The most widely studied RNA in relation to cancer is the micro RNA or miRNA. MiRNAs affect the expression of various genes which are linked to the cell cycle and there are reports that expression of miRNAs is associated with development of cancer. Infact miRNA profiling is useful to classify different types of cancer (Bannister, 2009). Some researchers have pointed to the fact that non-coding RNA which targets CpG islands in promoter regions acts in concert with histone methylation and DNA methylation to affect the transcription of genes which inturn contributes to cancer development. Such an implication needs more evidence -base (Ducasse and Brown, 2006). Conclusion Current research has implicated the role of epigenetics in the development of cancer. This aspect is interesting not only for the purpose of early diagnosis of the disease but also for treatment strategies like Anti-HDAC inhibition, reversal of DNA methylation, etc. However, the understanding of this subject is not yet clear and more research is warranted to ascertain and decipher the role of epigenetics in various types of cancers. It is hoped that a clear understanding of epigenetics can open a new aura in the treatment of various cancers. References Bannister, A. (2009). The role of epigenetics in cancer. ABCAM, University of Cambridge. Available at: http://www.abcam.com/index.html?pageconfig=resource&rid=10755&pid=10628 [Accessed 28th January, 2010] Baylain, S.B., and Herman, J.G. (2000). DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet., 16(4),168-74. Baylin, S.B., Esteller, M., Rountree, M.R., Bachman, K.E., Schuebel, K., and Herman, J.G. (2001). Aberrant patterns of DNA methylatio, chromatin formation and gene expression in cancer. Human Molecular Genetics, 10(7), 687- 692. Cang, S., Feng, J., Konno, S. (2009). Deficient histone acetylation and excessive deacetylase activity as epigenomic marks of prostate cancer cells. Int J Oncol., 35(6), 1417-22. Das, P.M., and Singal, R. (2004). DNA methylation and cancer. Journal of Clinical Oncology, 22(22), 4632-4642. Duccase, M., and Brown, M.A. (2006). Epigenetic aberrations and cancer. Molecular Cancer, 5, 60. Esteller, M., Corn, P.G., Baylin, S.B., Herman, J.G. (2001). A Gene Hypermethylation Profile of Human Cancer. Cancer Research., 61, 3225-3229. Jones, P.A., and Baylin, S.B. (2002). The fundamental role of epigenetic events in cancer. Genetics, 3, 415- 428. Mokarram, P., Kumar, K., Brim, H., Naghibalhossaini, F., Saberi-firoozi, M., Nouraie, M., et al. (2009). Distinct high-profile methylated genes in colorectal cancer. PLoS One., 4(9), e7012. Martin-Subero, J.I., Ammerpohl, O., Bibikova, M. (2009). A comprehensive microarray-based DNA methylation study of 367 hematological neoplasms. PLoS One., 4(9), e6986. Karray-Chouayekh, S., Trifa, F., Khabir, A., Boujelbane, N., Sellami-Boudawara, T., Daoud, J. (2009). J Biomed Biotechnol.2009, 369129. Kawamoto, K., Okino, S.T., Place, R.F. (2007). Epigenetic modifications of RASSF1A gene through chromatin remodeling in prostate cancer. Clin Cancer Res., 13(9), 2541-8. Hesson, L.B., Dunwell, T.L., Cooper, W.N., Catchpoole, D., Brini, A.T., Chiaramonte, R., (2009). The novel RASSF6 and RASSF10 candidate tumour suppressor genes are frequently epigenetically inactivated in childhood leukaemias. Mol Cancer, 8, 42. Vladimirova, V., Mikeska, T., Waha, A., Soerensen, N., Xu, J., Reynolds, P.C. (2009). Aberrant methylation and reduced expression of LHX9 in malignant gliomas of childhood. Neoplasia, 11(7), 700-11. Appendix Figure-1. Map of human genomes and sites of hypermethylated genes associated with cancer (Jones and Baylin, 2002) Figure-2 .Mechanism of hypermethylation of DNA contributing to tumorigenesis ((Jones and Baylin, 2002). Read More