JTCS Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Edmund S. Kassis
Dao M. Nguyen
David S. Schrump
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kassis, E. S.
Right arrow Articles by Schrump, D. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kassis, E. S.
Right arrow Articles by Schrump, D. S.
Related Collections
Right arrow Molecular biology

J Thorac Cardiovasc Surg 2006;131:298-306
© 2006 The American Association for Thoracic Surgery

General Thoracic Surgery

Depletion of DNA methyltransferase 1 and/or DNA methyltransferase 3b mediates growth arrest and apoptosis in lung and esophageal cancer and malignant pleural mesothelioma cells

Edmund S. Kassis, MD, Ming Zhao, MD, Julie A. Hong, MS, G. Aaron Chen, MS, Dao M. Nguyen, MD, David S. Schrump, MD *

Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Md.

Read at the Eighty-fifth Annual Meeting of The American Association of Thoracic Surgery, San Francisco, Calif, April 10-13, 2005.

Received for publication April 8, 2005; accepted for publication May 20, 2005.

* Address for reprints: David S. Schrump, MD, Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, Building 10, Room 4-3942, 10 Center Dr MSC 1201, Bethesda, MD 20892. (Email: david_schrump{at}nih.gov).

OBJECTIVE: DNA methyltransferase (DNMT)1, DNMT3b, or both, facilitate malignant transformation through chromatin remodeling mechanisms. The present study was undertaken to examine the effects of antisense-mediated inhibition of DNMT expression in cultured thoracic malignancies.

METHODS: CALU-6 and A549 lung cancer, SKGT5 and BIC esophageal adenocarcinoma, and H2373 and H2052 malignant pleural mesothelioma (MPM) cells, as well as normal human bronchial epithelial (NHBE) cells, were transfected with phosphorothioate-modified antisense oligos targeting DNMT1, DNMT3b, or both, or mismatch oligos. Quantitative reverse transcription–polymerase chain reaction, Western blotting, trypan blue exclusion, and ApoBrdU techniques were used to evaluate DNMT expression, proliferation, and apoptosis after antisense oligo transfections. Gene expression profiles were assessed by using long-oligo array techniques.

RESULTS: Antisense oligos mediated specific and dose-dependent depletion of DNMT1 and DNMT3b, resulting in pronounced inhibition of proliferation of all thoracic cancer lines, but not NHBE cells. Depletion of DNMT1 or DNMT3b coincided with dramatic, caspase-dependent, p53-independent apoptosis in 4 of the 6 thoracic cancer lines. The antiproliferative effects of the antisense oligos were not attributable to induction of RASSF1A, p16, or p21 tumor suppressor genes, and did not coincide with demethylation of genes encoding cancer-testis antigens. DNA methyltransferase knockdown mediated induction of numerous genes regulating response to genotoxic stress. Gene expression profiles after DNMT1, DNMT3b, or combined DNMT1/3b depletion were remarkably similar, yet distinctly different from expression profiles mediated by 5 aza 2' deoxycytidine.

CONCLUSIONS: Antisense oligos targeting DNMT1 and DNMT3b induce genomic stress, and mediate potent growth inhibition in lung and esophageal cancer and MPM cells. These findings support further evaluation of DNMT knockdown strategies for cancer therapy.

Abbreviations and Acronyms ASO = antisense oligo; DAC = 5 aza 2' deoxycytidine; DNMT = DNA methyltransferase; HDAC = histone deacetylase; MM = mismatch; MPM = malignant pleural mesothelioma; NHBE cell = Normal human bronchial epithelial cell; RT-PCR = reverse transcription–polymerase chain reaction




This article has been cited by other articles:


Home page
 Evid Based Complement Alternat MedHome page
C.-J. Yao, C.-M. Yang, S.-E. Chuang, J.-L. Yan, C.-Y. Liu, S.-W. Chen, K.-H. Yan, T.-Y. Lai, and G.-M. Lai
Targeting PML-RAR{alpha} and Oncogenic Signaling Pathways by Chinese Herbal Mixture Tien-Hsien Liquid in Acute Promyelocytic Leukemia NB4 Cells
Evid. Based Complement. Altern. Med., November 6, 2009; (2009) nep165v1.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. A. Damiani, C. M. Yingling, S. Leng, P. E. Romo, J. Nakamura, and S. A. Belinsky
Carcinogen-Induced Gene Promoter Hypermethylation Is Mediated by DNMT1 and Causal for Transformation of Immortalized Bronchial Epithelial Cells
Cancer Res., November 1, 2008; 68(21): 9005 - 9014.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS
Copyright © 2006 by The American Association for Thoracic Surgery.