Unique Role for a DNA Methyltransferase Isoform in Lung Cancer

Aberrant DNA methylation patterns are one of the most studied epigenetic components in cancer development. In certain cancers, altered expression of DNA methyltransferase (DNMT) family members could potentially cause this DNA methylation re-patterning. Specifically, DNMT3B has over thirty different isoforms with varied expression in tissues (Ostler et al. 2007). Recent studies have shown that DNMT3B is responsible for gene body methylation by recognizing the H3K36me3 modification found in gene bodies, especially gene body remethylation after treatment with a DNAmethylation inhibitor (5-Aza-CdR) (Baubec et al. 2015; Yang et al. 2014). The methylated gene bodies showedpositive correlationswith gene expression and, additionally, hypomethylation of gene bodies could lead to down regulation of gene expression (Yang et al. 2014). Non-small cell lung cancer (NSCLC) is one such disease which has overexpression of DNMT3B, including a specific subfamily which lacks an N-terminal domain (ΔDNMT3B) (Wang et al. 2006). In this issue of EBioMedicine the work presented by Ma et al. (Ma et al. 2015), provides exciting developments for NSCLC with findings connecting the aberrant DNA methylation patterns during tumorigenesis with the predominantly expressed DNMT3B isoform: ΔDNMT3B4-del, a truncated DNMT3B isoform lacking exons 21 and/or 22 which contain the catalytic domain. DNMTs responsible for DNA methylation establishment include: DNMT1, DNMT3A and DNMT3B, as well as DNMT3L (DNAmethyltransferase 3-like). DNMT3A and B are the de novo methyltransferases responsible for developing new methylation patterns in the genome as well as maintenance of stable gene silencing related to key biological processes. Generally, tumorigenesis involves DNA hypermethylation at CpG islands (CGI) as well as global DNA hypomethylation (Jones 2012). Although there are many studies that focus on a specific DNMT and their role during development and cancer, there is still a knowledge gap with respect to how the plethora of DNMT isoforms contributes to DNA methylation alterations. The work by Ma et al. builds on the foundation that primary NSCLC tumors aberrantly express ΔDNMT3B from earlier studies with ΔDNMT3B4 being the most prevalent isoform (Wang et al. 2007). Additionally, ΔDNMT3B4 can have a truncated methyltransferase domain (ΔDNMT3B4-del) that was shown to facilitate DNA methylation changes in transgenicmice similar to early initiating events in tumorigenesis. Interestingly, approximately half of the NSCLC tumors