∆DNMT3B4-del Contributes to Aberrant DNA Methylation Patterns in Lung Tumorigenesis
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 i...
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| Format: | Article |
| Language: | English |
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Elsevier
2015-10-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396415301249 |
| _version_ | 1818193838726971392 |
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| author | Mark Z. Ma Ruxian Lin José Carrillo Manisha Bhutani Ashutosh Pathak Hening Ren Yaokun Li Jiuzhou Song Li Mao |
| author_facet | Mark Z. Ma Ruxian Lin José Carrillo Manisha Bhutani Ashutosh Pathak Hening Ren Yaokun Li Jiuzhou Song Li Mao |
| author_sort | Mark Z. Ma |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T00:52:46Z |
| format | Article |
| id | doaj.art-06f71702b5c348ceae59009db2ea786a |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-12T00:52:46Z |
| publishDate | 2015-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-06f71702b5c348ceae59009db2ea786a2022-12-22T00:43:57ZengElsevierEBioMedicine2352-39642015-10-012101340135010.1016/j.ebiom.2015.09.002∆DNMT3B4-del Contributes to Aberrant DNA Methylation Patterns in Lung TumorigenesisMark Z. Ma0Ruxian Lin1José Carrillo2Manisha Bhutani3Ashutosh Pathak4Hening Ren5Yaokun Li6Jiuzhou Song7Li Mao8Department of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, University of Maryland, 650 W Baltimore St, Baltimore, MD 21201, USADepartment of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, University of Maryland, 650 W Baltimore St, Baltimore, MD 21201, USADepartment of Animal and Avian Sciences, University of Maryland, College Park, Silver Spring, MD 20742, USADepartment of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Carolinas Healthcare System, Charlotte, NC, USATeva Pharmaceuticals, 1090 Horsham Rd, North Wales, PA 19454, USADepartment of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, University of Maryland, 650 W Baltimore St, Baltimore, MD 21201, USACollege of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, PR ChinaDepartment of Animal and Avian Sciences, University of Maryland, College Park, Silver Spring, MD 20742, USADepartment of Oncology and Diagnostic Sciences, University of Maryland School of Dentistry, University of Maryland, 650 W Baltimore St, Baltimore, MD 21201, USAAberrant 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.http://www.sciencedirect.com/science/article/pii/S2352396415301249DNMT3BΔDNMT3BΔDNMT3B-delDNA methylationLung cancerMouse modelTumorigenesis |
| spellingShingle | Mark Z. Ma Ruxian Lin José Carrillo Manisha Bhutani Ashutosh Pathak Hening Ren Yaokun Li Jiuzhou Song Li Mao ∆DNMT3B4-del Contributes to Aberrant DNA Methylation Patterns in Lung Tumorigenesis EBioMedicine DNMT3B ΔDNMT3B ΔDNMT3B-del DNA methylation Lung cancer Mouse model Tumorigenesis |
| title | ∆DNMT3B4-del Contributes to Aberrant DNA Methylation Patterns in Lung Tumorigenesis |
| title_full | ∆DNMT3B4-del Contributes to Aberrant DNA Methylation Patterns in Lung Tumorigenesis |
| title_fullStr | ∆DNMT3B4-del Contributes to Aberrant DNA Methylation Patterns in Lung Tumorigenesis |
| title_full_unstemmed | ∆DNMT3B4-del Contributes to Aberrant DNA Methylation Patterns in Lung Tumorigenesis |
| title_short | ∆DNMT3B4-del Contributes to Aberrant DNA Methylation Patterns in Lung Tumorigenesis |
| title_sort | ∆dnmt3b4 del contributes to aberrant dna methylation patterns in lung tumorigenesis |
| topic | DNMT3B ΔDNMT3B ΔDNMT3B-del DNA methylation Lung cancer Mouse model Tumorigenesis |
| url | http://www.sciencedirect.com/science/article/pii/S2352396415301249 |
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