∆ DNMT3B4-del Contributes to Aberrant DNA Methylation Patterns in Lung Tumorigenesis

• DNMT3B/∆DNMT3B-del is the predominantly expressed isoform in a large number of lung cancers.
• ∆ DNMT3B4-del can cause aberrant DNA methylation patterns similar to tumorigenesis.
• ∆ DNMT3B4-del facilitates carcinogen-induced lung tumorigenesis in a mouse model.Lung cancer is the leading cause of cancer-related deaths in the United States. Epigenetic alterations, particularly alterations in DNA methylation patterns, play critical roles in lung tumorigenesis. We show that DNMT3B/ΔDNMT3B-del is predominantly expressed in a significant percentage of lung cancers including both cell lines and primary tumors. We demonstrate that ΔDNMT3B4-del is critical in the formation of aberrant DNA methylation patterns in mouse lungs similar to human lung cancers and contributes to neoplasia formation when exposed to carcinogens, supporting ΔDNMT3B4-del as a novel target for lung cancer prevention.

Aberrant DNA methylation is a hallmark of cancer but mechanisms contributing to the abnormality remain elusive. We have previously shown that ∆DNMT3B is the predominantly expressed form of DNMT3B. In this study, we found that most of the lung cancer cell lines tested predominantly expressed DNMT3B isoforms without exons 21, 22 or both 21 and 22 (a region corresponding to the enzymatic domain of DNMT3B) termed DNMT3B/∆DNMT3B-del. In normal bronchial epithelial cells, DNMT3B/ΔDNMT3B and DNMT3B/∆DNMT3B-del displayed equal levels of expression. In contrast, in patients with non-small cell lung cancer NSCLC), 111 (93%) of the 119 tumors predominantly expressed DNMT3B/ΔDNMT3B-del, including 47 (39%) tumors with no detectable DNMT3B/∆DNMT3B. Using a transgenic mouse model, we further demonstrated the biological impact of ∆DNMT3B4-del, the ∆DNMT3B-del isoform most abundantly expressed in NSCLC, in global DNA methylation patterns and lung tumorigenesis. Expression of ∆DNMT3B4-del in the mouse lungs resulted in an increased global DNA hypomethylation, focal DNA hypermethylation, epithelial hyperplastia and tumor formation when challenged with a tobacco carcinogen. Our results demonstrate ∆DNMT3B4-del as a critical factor in developing aberrant DNA methylation patterns during lung tumorigenesis and suggest that ∆DNMT3B4-del may be a target for lung cancer prevention.