Genes Suppressed by DNA Methylation in Non-small Cell Lung Cancer Reveal the Epigenetics of Epithelial-mesenchymal Transition

Overview

Journal BMC Genomics

Publisher Biomed Central

Specialty Genetics

Date 2014 Dec 10

PMID 25486910

Citations 31

Authors

Steven H Lin

Jing Wang

Pierre Saintigny

Chia-Chin Wu

Uma Giri

Jing Zhang

Toshi Menju

Lixia Diao

Lauren Byers

John N Weinstein

Kevin R Coombes

Luc Girard

Ritsuko Komaki

Ignacio I Wistuba

Hiroshi Date

John D Minna

John V Heymach

Affiliations

Soon will be listed here.

Abstract

Background: DNA methylation is associated with aberrant gene expression in cancer, and has been shown to correlate with therapeutic response and disease prognosis in some types of cancer. We sought to investigate the biological significance of DNA methylation in lung cancer.

Results: We integrated the gene expression profiles and data of gene promoter methylation for a large panel of non-small cell lung cancer cell lines, and identified 578 candidate genes with expression levels that were inversely correlated to the degree of DNA methylation. We found these candidate genes to be differentially methylated in normal lung tissue versus non-small cell lung cancer tumors, and segregated by histologic and tumor subtypes. We used gene set enrichment analysis of the genes ranked by the degree of correlation between gene expression and DNA methylation to identify gene sets involved in cellular migration and metastasis. Our unsupervised hierarchical clustering of the candidate genes segregated cell lines according to the epithelial-to-mesenchymal transition phenotype. Genes related to the epithelial-to-mesenchymal transition, such as AXL, ESRP1, HoxB4, and SPINT1/2, were among the nearly 20% of the candidate genes that were differentially methylated between epithelial and mesenchymal cells. Greater numbers of genes were methylated in the mesenchymal cells and their expressions were upregulated by 5-azacytidine treatment. Methylation of the candidate genes was associated with erlotinib resistance in wild-type EGFR cell lines. The expression profiles of the candidate genes were associated with 8-week disease control in patients with wild-type EGFR who had unresectable non-small cell lung cancer treated with erlotinib, but not in patients treated with sorafenib.

Conclusions: Our results demonstrate that the underlying biology of genes regulated by DNA methylation may have predictive value in lung cancer that can be exploited therapeutically.

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References

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Cheng H, Fukushima T, Takahashi N, Tanaka H, Kataoka H . Hepatocyte growth factor activator inhibitor type 1 regulates epithelial to mesenchymal transition through membrane-bound serine proteinases. Cancer Res. 2009; 69(5):1828-35. DOI: 10.1158/0008-5472.CAN-08-3728. View

Wales M, Biel M, El Deiry W, Nelkin B, Issa J, Cavenee W . p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nat Med. 1995; 1(6):570-7. DOI: 10.1038/nm0695-570. View

Brock M, Hooker C, Ota-Machida E, Han Y, Guo M, Ames S . DNA methylation markers and early recurrence in stage I lung cancer. N Engl J Med. 2008; 358(11):1118-28. DOI: 10.1056/NEJMoa0706550. View

Toyota M, Suzuki H, Yamashita T, Hirata K, Imai K, Tokino T . Cancer epigenomics: implications of DNA methylation in personalized cancer therapy. Cancer Sci. 2009; 100(5):787-91. PMC: 11159488. DOI: 10.1111/j.1349-7006.2009.01095.x. View

Ding L, Xie Y, Park S, Xiao G, Story M . Enhanced identification and biological validation of differential gene expression via Illumina whole-genome expression arrays through the use of the model-based background correction methodology. Nucleic Acids Res. 2008; 36(10):e58. PMC: 2425463. DOI: 10.1093/nar/gkn234. View

Maier S, Dahlstroem C, Haefliger C, Plum A, Piepenbrock C . Identifying DNA methylation biomarkers of cancer drug response. Am J Pharmacogenomics. 2005; 5(4):223-32. DOI: 10.2165/00129785-200505040-00003. View

Swafford D, Middleton S, Palmisano W, Nikula K, Tesfaigzi J, Baylin S . Frequent aberrant methylation of p16INK4a in primary rat lung tumors. Mol Cell Biol. 1997; 17(3):1366-74. PMC: 231861. DOI: 10.1128/MCB.17.3.1366. View

Noro R, Gemma A, Miyanaga A, Kosaihira S, Minegishi Y, Nara M . PTEN inactivation in lung cancer cells and the effect of its recovery on treatment with epidermal growth factor receptor tyrosine kinase inhibitors. Int J Oncol. 2007; 31(5):1157-63. View

10.

Jones P, Baylin S . The epigenomics of cancer. Cell. 2007; 128(4):683-92. PMC: 3894624. DOI: 10.1016/j.cell.2007.01.029. View

11.

Yang J, Weinberg R . Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008; 14(6):818-29. DOI: 10.1016/j.devcel.2008.05.009. View

12.

Ibanez de Caceres I, Cortes-Sempere M, Moratilla C, Machado-Pinilla R, Rodriguez-Fanjul V, Manguan-Garcia C . IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer. Oncogene. 2009; 29(11):1681-90. DOI: 10.1038/onc.2009.454. View

13.

Smoot M, Ono K, Ruscheinski J, Wang P, Ideker T . Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics. 2010; 27(3):431-2. PMC: 3031041. DOI: 10.1093/bioinformatics/btq675. View

14.

Singh A, Greninger P, Rhodes D, Koopman L, Violette S, Bardeesy N . A gene expression signature associated with "K-Ras addiction" reveals regulators of EMT and tumor cell survival. Cancer Cell. 2009; 15(6):489-500. PMC: 2743093. DOI: 10.1016/j.ccr.2009.03.022. View

15.

Chen M, Xie Y, Story M . An Exponential-Gamma Convolution Model for Background Correction of Illumina BeadArray Data. Commun Stat Theory Methods. 2011; 40(17):3055-3069. PMC: 3137271. DOI: 10.1080/03610921003797753. View

16.

Taniguchi T, Tischkowitz M, Ameziane N, Hodgson S, Mathew C, Joenje H . Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nat Med. 2003; 9(5):568-74. DOI: 10.1038/nm852. View

17.

Sproul D, Nestor C, Culley J, Dickson J, Dixon J, Harrison D . Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer. Proc Natl Acad Sci U S A. 2011; 108(11):4364-9. PMC: 3060255. DOI: 10.1073/pnas.1013224108. View

18.

Kim E, Hong W, Lee J, Mao L, Morice R, Liu D . Biological activity of celecoxib in the bronchial epithelium of current and former smokers. Cancer Prev Res (Phila). 2010; 3(2):148-59. PMC: 4028718. DOI: 10.1158/1940-6207.CAPR-09-0233. View

19.

Shames D, Girard L, Gao B, Sato M, Lewis C, Shivapurkar N . A genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies. PLoS Med. 2006; 3(12):e486. PMC: 1716188. DOI: 10.1371/journal.pmed.0030486. View

20.

Mani S, Guo W, Liao M, Eaton E, Ayyanan A, Zhou A . The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008; 133(4):704-15. PMC: 2728032. DOI: 10.1016/j.cell.2008.03.027. View