Epigenetic Therapies for Cancer

Abstract

At the cellular level, cancers originate from the monoclonal expansion of a mutant cell leading to accumulation of aberrant cells that continue to lose differentiated features and acquire different biological properties in their progression toward disseminated or metastatic disease. The onset and progression of cancer involves genomic derangements that can be manifested in two ways: 1) Genetic and gross structural defects (e.g. single nucleotide polymorphism (SNP), classic deletion, insertion mutation, chromosomal deletion/inversion/translocation, allelic loss/gain, gene amplification/ deletion), and 2) Aberrant epigenetic covalent modifications (e.g. DNA methylation, histone acetylation, methylation, phosphorylation, citrullination, sumolyation, and ADP ribosylation). Genomic instability can be triggered by chemical carcinogens, radiation, stress, oncogenic DNA viruses and the aging process. In almost all cancers, genomic instability in the form of genetic alterations or epigenetic modifications affects four classes of genes: oncogenes, tumor suppressor genes, apoptotic genes and/or DNA repair genes. Oncogenes encode proteins that function as positive proliferative signals for tumors. Tumor suppressor genes negatively regulate cell proliferation and are inactivated in many tumors. Apoptotic genes encode proteins that instruct the cell to commit suicide, while DNA repair genes encode proteins that maintain the fidelity of DNA sequences during transcription and replication. The uncontrolled expression of oncogenes or the silencing of tumor suppressor genes can lead to immortalization of cells. For example, in neuroblastoma, the overexpresssion of Nmyc oncogene correlates with aggressive tumor behavior (Seeger et al., 1985). The ras oncogene is activated in more than half of the tumors studied in humans (Barbacid et al., 1987), and both relapse and decreased survival in breast cancer patients have been associated with overexpression of Her-2 oncogene (Slamon et al., 1987). The tumor suppressor and cell cycle regulator gene, p53, is mutated or deleted in more than 50% of human tumors (Hollstein M et al., 1991). p53 gene is described as the guardian of the genome because it can activate DNA repair genes when DNA is damaged, or induce apoptosis when DNA damage is sensed to be irreparable. Despite the presence of defective genes in tumors, tumors actually arise through many different combinations of genetic alterations. The phenotypic diversity observed between normal and cancer cells cannot be explained simply by structural and genetic alterations. Epigenetic mechanisms have been shown to activate or inactivate genes. Conrad Waddington first coined the term epigenetic to mean changes above and beyond (epi) the primary DNA sequence (Waddington, 1939). The term epigenetic refers to heritable genetic