Regulation Of DNA Methylation By UHRF2 As A Mechanism For DNA Hypomethylation In Cancer

Epigenetics is a fast emerging area of study in genetics. It can be referred as a study of heritable changes in gene expression without any change in the underlying DNA sequence. Such changes are involved in the processes of development and cellular differentiation. DNA methylation is one of the critical epigenetic modifications in the mammalian genome. It is involved in regulating many cellular processes, which include embryonic development, transcription, chromatin structure, X chromosome inactivation, genomic imprinting and chromosome stability. DNA methylation patterns are established and maintained not only by a group of enzymes known as the DNA methyltransferases (DNMTs), but also by several proteins which can ’read’ the methylation marks. UHRF1 is one of such proteins, which plays important roles in DNA methylation maintenance. UHRF2, another member of the UHRF family proteins, is highly similar to UHRF1 in both sequence and structure, raising questions about its role in DNA methylation.Although previouse sudies indicated that UHRF2 cannot substitute for UHRF1 and plays no role in DNA maintaince methylation. We have demonstrated in this study that UHRF2 is a negative regulator of DNA methylation and does so by inhibiting de novo DNA methylation via inducing DNMT3 A degradation. Subsequent analysis of lung cancer lines revealed a general inverse correlation between UHRF2 +and DNMT3A.We observed that in lung cancer A549 cell line knock down of UHRF2 led to increase level of DNMT3A and impaired tumorigenesis in nude mice.Similarly,over-expression of the wild-type but not enzymatic deficient mutant DNMT3A in A549 cells result in impaired tumorigenesis in nude mice. Together these results indicate that UHRF2 negatively regulate de nove DNA methylation and affect cancer progression.