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Epigenetics and Cancer by Prof. Dr. Motawa E. El Houseini

Epigenetics and Cancer by Prof. Dr. Motawa E. El Houseini. Genome: It is a series of functional unit of genes, each of which contains the information for a single function. The genes were expressed via mRNA and translated to proteins which carry out the biological activities of the cells.

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Epigenetics and Cancer by Prof. Dr. Motawa E. El Houseini

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  1. Epigenetics and Cancerby Prof. Dr. Motawa E. El Houseini Genome: It is a series of functional unit of genes, each of which contains the information for a single function. The genes were expressed via mRNA and translated to proteins which carry out the biological activities of the cells. The gene is structural unit of the genome which contains the following regions: - Promoter region. -Enhancer. -Silencer sequence.

  2. Definition: • Epigenetics represents the science for the studying heritable changes of DNA, not involving changes in DNA sequence that regulate gene expression. • There are at least two forms of information in the genome of the cell. • A- Genetic information • B- Epigenetic information

  3. The former provides the building block for the manufacture of all Proteins needed for the cell functional activity. • The latter provides additional instruction on how, when and where these information should be used.

  4. Biochemical reactions which are operating in Epigenetics 1- DNA methylation and demethylation 2- Histone acetylation and deacetylation. 3- Histone methylation and demethylation 4- Phosphorylation and dephosphorylation of histones and non-histone proteins

  5. Biochemical reactions which are operating in Epigenetics 1- DNA methylation and demethylation 2- Histone acetylation and deacetylation. 3- Histone methylation and demethylation 4- Phosphorylation and dephosphorylation of histones and non-histone proteins

  6. First DNA methylation • It is the covalent addition of methyl group to 5th Position of cystosine with in CPG di-nucleotides which are frequently located in the promoter region of genes. • It is a complex process catalyzed by DNA methyl transferase. The addition of the methyl group from the universal methyl Donor s-adenosyl L -methionine.

  7. Epigonome and acetylation Epigenetic changes of the genome include: A- DNA methylation as mentioned before. B- Chromatin remodeling by histone modification by acetylation. The acetylation of histones (H) mainly H3 and H4 is done at A.A lysine 9 & 14 and lysine 5, 8, 12, 16 respectively by enzyme systems histone acetyltransferases.

  8. The latter transfer the acetyl co-enzyme A to the lysine residue which leads to neutralizing the positive charge. Histone acetylation loosens chromatin packaging and correlates with transcriptional activation. Whereas, histone deacetylases remove the acetyl groups re-establishing the positive charge in the histones which are associated with repression of transcription.

  9. Histone methylation The process is carried out by an enzyme histone methyl transferase which directs site-specific methylation of amino-acid residues such as lys. 4&9 in the tail of the histone H3.

  10. - Methylation of lysine 9 in histone H3 directs the binding of non-coding RNA, histone deacetylase to control chromatin structure and gene expression.

  11. Neoplastic Transformation It is a complex multi-event and multi-stage Process. • The process can be divided into two requisite sequences 1- Neoplastic conversion 2- Neoplastic development The stages of the process can be shown as Follow:

  12. Neoplastic Conversion Chemical Carcinogen Progression -DNA Reactive Promotion -Epigenetic effect -DNA methylation -Histone deacetylation Neoplastic cell Genetic and epigenetic Levels DNA alteration Neoplastic Development

  13. Genes promoters hypermethylation in human cancers - The list of genes that are found to be inactivated by DNA methylation events is growing rapidly and includes genes involved in the following : A- Signal transduction cascade pathways. B- Cell cycle regulation. C-Angiogenesis. D-Apoptosis. E- DNA repair.

  14. Recent Cancer methylation studies predict that hundred (100) of CPG islands could be methylated in a tumor cell. However, it is clear that both the genome-wide methylation studies and candidate gene approaches that each tumor type may have its own set of cancer cell type specific genes that are more susceptible to methylation. Thus each cancer type may have the potential to be typed or classified according to methylation profile.

  15. P 15/P16 Methylation in cancer • Aberrant methylation of cycline dependent kinase inhibitor P16 INK 4a has been frequently detected in many human cancers. - P15INK4b gene adjacent to P16 on chromosome q p21, is also commonly hyper-methylated in human neoplasm, (Hematological malignancies and head and neck sequamous cell carcinoma).

  16. - The differential levels of methylated P16 and P15 in plasma might be potential useful markers in screening high risk population for an early detection of head and neck squamous cell carcinoma.

  17. In colorectal cancer: - Progressive methylation of DNA and subsequent silencing of a subset of genes occurs in normal tissues along side age and time dependent events which predispose these normal cells to neoplastic transformation.

  18. Cytosine methylation of CPG loci underlies many of the genetic events in colorectal carcinogenesis which can be discovered in very early stage. The inactivation of adenomatous polyposis coli (Apc): • The gene is believed to initiate colorectal carcinogenesis in 80% of the cases therefore, it has potential as sensitive marker of on early stage of the disease.

  19. In lung cancer • It has been shown that a panel of markers, for aberrant methylation that detects lung cancer at the early stages of development has been observed. • This panel includes the following genes: -P 16 -APC -G-ST -E-cadhrin

  20. - In breast cancer • BRCA gene is a breast cancer susceptibty gene, that is tumor suppressor gene responsible for both normal development and carcinogenesis in breast. • BRCA1, reveals multi functional protein involved in DNA repair. Cell cycle regulation, transcription and apoptosis • BRCA1 mutations may play a significant role in the tumor-genesis of familial breast cancer.

  21. Aberrant methylation of BRCA1 CPG island Promoter is associated with decreased BRCA1 mRNA in sporadic breast cancer cells.

  22. There is a strong relationship between BRCA1 promoter hyper-methylation and the existence of LOH (loss of hetero-zygosity) at the BRCA locus. This finding suggested that one allele has been lost by deletion and the other is inactivated by aberrant methylation. Both events simultaneously leading to the bi-allelic inactivation and complete lack of function of the BRCA1 gene.

  23. The frequent loss of BRCA1 protein In sporadic breast carcinoma could also result from epigenetic inactivation of both parental alleles. Reduced BRCA1 protein expression in tumors of patients with poor survival prognosis provides the evidence of this protein as a prognostic factor in patients with sporadic breast carcinoma.

  24. Therapeutic Targets of Epigenome • Targeting DNA methylation and histone acetylation. • Decitabine drug (5 – AZa-2 deoxycytidine) has been widely used as a demethylating agent in vitro and is used clinically in the treatment of acute leukemias and myelodysplasia. • Therapetuc strategy was preceded in animal model using anti-sense oligonuleotides against DNA methyl transferase. The studies showed an inhibition of tumor growth and re-expression of p16 in treated animals. • Combination of histone deacetylase inhibitors (HDAC) e.g. Trichostatin and DNA methy-transferase inhibitor decitabine exerts a synergistic effect on the re-expression of hyper methylated silenced genes such as p15, TIMP and DNA mismatch repair genes.

  25. Epigenome in relation to cancer drug resistance • Intrinsic and acquired drug resistance remain the most unpredictable factor affecting chemotherapy. DNA hypermethylation has been found to be associated with drug resistance acquired during cancer chemotherapy and therefore, re-expression of methylation-silenced genes resulted in increased sensitivity to existing chemotherapy.

  26. Example: Many chemotherapeutic agents kill cancer cells through induction of apoptosis accordingly; deregulation of any gene involved in the activation of the apoptotic process may be a major mechanism of chemo-resistance. Thus treatment of cancer cells with demethylating agent (decitobine) could lead to re-expression of caspase 8 and restore the sensitivity to the chemotherapy. • This suggests that targeting the silencing mechanism of apoptosis related genes may increase the efficacy of various cancer chemotherapy.

  27. CONCLUSION • Hyper methylation of CPG islands associated With tumor suppressor genes has been proposed to contribute to carcinogenesis. • Epigenetic markers open new avenues for an early detection, diagnosis , prognosis as well as therapeutic targets in cancers.

  28. DNA demethylating agents and histone deacetylase inhibitors are underway to awake those silent tumor suppressor genes for a better treatment of patients suffering from cancers .

  29. Epigenetic wins over genetics: induction of differentiation in tumor cells. Semin Cancer Biol. 2002 Oct;12(5):339-46 Lotem J, Sachs L. • Genome-wide analysis of epigenetics in cancer ann N Y Acad Sci. 2003 Mar, 983:101-9 Lee Mp.

  30. Epigenetics in carcinogenesis and cancer prevention Ann NY Acad sci.2003 Mar;983:213-9. Jones PA. • Angiogenesis and the role of epigenetics in metastasis Clin Exp Metastasis. 2003;20 (3): 215-27. Coomber Bl, Yu JL, Fathers KE, Plumb C, Rak JW.

  31. Epigenetics in cancer prevention: early detection and risk assessment: introduction. Ann NY Acad Sci.2003 Mar; 984:1-4. Dunn BK, Verma M, Umar A. Relevance of DNA methylation in the management of cancer. Lancet Oncol. 2003 Jun; 4(6):351-8. Esteller M. Transcriptional silencing of the DLC-1 tumor suppressor gene by epigenetic mechanism in gastric cancer cells. Oncogene 2003 Jun 19;22(25):3943-51. Kim Ty, Jong HS, Song SH, Dimtchev A,Heong SJ, Lee JW, Kim TY, Kim NK, Jung M, Bang YJ.

  32. Mutation analysis of novel human liver-related putative tumor suppressor gene in hepatocellular carcinoma. World J Gastroenterol. 2003 Jan;9(1):89-93. Liao C, Zhao MJ, Zhao J, Song H, Pineau P, Marchio A, Dejean A, Tiollais P, Wang HY, Li TP. Viral genes and methylation. Ann N Y Acad Sci. 2003 Mar; 983:170-80 Verma M.

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