In normal cells, repetitive DNA is hypermethylated and transcriptionally silent, whereas transcribed gene promoters are undermethylated and associated with active, open chromatin.  Cancer cells exhibit abnormal patterns of DNA methylation, which is hypothesized to contribute to the genesis of cancer in at least two ways:  (i) repetitive DNA sequences in cancer cells become hypomethylated and transcriptionally active and (ii) aberrant methylation of promoter regions results in transcriptional silencing of tumor suppressor genes. Consequently, modulation of DNA methylation patterns in cancer cells presents an attractive target for the development of novel cancer therapeutics.  

Dr. Lucy Godley and colleagues at the University of Chicago have identified cancer-specific forms of DNA methyltransferase (DNMT) 3B in 24/25 cancer cell lines and 30 primary leukemias.  These DNMT3B mutants are the result of aberrant splicing at the 5�end of the gene, often causing retention of intronic sequence in the mRNA that are absent in the wild type transcript.  These aberrant transcripts are translated into abnormal DNMT3B proteins, resulting in altered methylation patterns in the cancer cells.  Dr. Godley�s group has shown that RNAi mediated targeting of the intronic sequence of DNMT3B7 mRNA (a specific intronic variant present in all of the primary leukemic samples tested) resulted in destruction of the cancer-specific mRNA without any effect on wild-type DNMT3B mRNA. Expression of a shRNA targeting the intron sequence of DNMT3B7 mRNA resulted in a reduction in the growth rate of a well characterized cancer cell line.  Targeting of cancer-specific DNMT3B variants through RNAi or small molecules therefore presents an attractive strategy for selectively targeting and correcting the abnormal methylation pattern in cancer cells.

File Number: 1447 

Web site: http://biomed.bsd.uchicago.edu/common/faculty/g...