Roles of the DNA methylation machinery in cellular transformation and tumorigenesis

DNA methylation is vital in genome functions as diverse as parental imprinting, X chromosome inactivation, regulation of gene expression and precipitation of inactive chromatin structures. A growing line of evidence suggests that aberrations in proper homeostatic regulation of genomic methylation status are causal in oncogenic processes. Recent evidence has also revealed novel roles of the DNA Methyltransferase (DNMT1), the enzyme believed to be largely responsible for maintenance of the DNA methylation pattern, in replication and in direct regulation of chromatin structure which may help to explain its role in cancer. Despite the importance of DNMT1 in the regulation in many critical genome functions, little has been done to clearly elucidate its regulation of expression. Chapters 1--3 of this thesis describe three intriguing mechanisms employed in the regulation of dnmt1 gene expression which further implicate this protein as an important player in cellular transformation and tumorigenesis. Chapter 1 describes dnmt1 as a novel downstream effector of the commonly studied T Antigen oncogenic signaling pathway and points to a novel mechanism by which DNMT1 inhibitors might target tumorigenesis. dnmt1 has also been previously characterized as an effector of the Ras-jun oncogenic signaling pathway and Chapter 2 describes how the c-jun proto-oncogene can recruit and synergize with the tumor suppressor Rb to transactivate dnmt1. Chapter 3 describes a novel and unique mechanism by which dnmt1 can feedback regulate its own expression via methylation of its own promoter. The discovery of active demethylation activity in transformed cell types has also changed our understanding of genomic methylation as a means of epigenetic control and suggests the possibility that aberrant regulation of a demethylase gene may also contribute to cellular transformation and tumorigenesis. Chapter 4, therefore, describes the upregulation of Mbd2/Demethylase in various human tumors and the inhibition of tumorigenesis observed in vitro and in vivo upon treatment with Mbd2/Demethylase antisense inhibition. These results point towards a critical role for the methylation machinery and homeostatic control of the genomic methylation status in cancer and suggest a strong potential for anticancer therapeutics which target the DNA methylation machinery.