ANK1 Methylation regulates expression of MicroRNA-486-5p and discriminates lung tumors by histology and smoking status

Mathewos Tessema, Christin M. Yingling, Maria A. Picchi, Guodong Wu, Tyrone Ryba, Yong Lin, Aaron O. Bungum, Eric Edell, Avrum Spira, Steven A. Belinsky

Research output: Contribution to journalArticle

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Abstract

The intragenic tumor-suppressor microRNA miR-486-5p is often down-regulated in non-small cell lung cancer (NSCLC) but the mechanism is unclear. This study investigated epigenetic co-regulation of miR-486-5p and its host gene ANK1. MiR-486-5p expression in lung tumors and cell lines was significantly reduced compared to normal lung (p < 0.001) and is strongly correlated with ANK1 expression. In vitro, siRNA-mediated ANK1 knockdown in NSCLC cells also reduced miR-486-5p while the DNA methylation inhibitor 5-aza-2′-deoxycytidine induced expression of both. ANK1 promoter CpG island was unmethylated in normal lung but methylated in 45% (118/262) lung tumors and 55% (17/31) NSCLC cell lines. After adjustment for tumor histology and smoking, methylation was significantly more prevalent in adenocarcinoma (101/200, 51%) compared to squamous cell carcinoma (17/62, 27%), p < 0.001; HR = 3.513 (CI: 1.818–6.788); and in smokers (73/128, 57%) than never-smokers (28/72, 39%), p = 0.014; HR = 2.086 (CI: 1.157–3.759). These results were independently validated using quantitative methylation data for 809 NSCLC cases from The Cancer Genome Atlas project. Together, our data indicate that aberrant ANK1 methylation is highly prevalent in lung cancer, discriminate tumors by histology and patients' smoking history, and contributes to miR-486-5p repression.

Original languageEnglish (US)
Pages (from-to)191-200
Number of pages10
JournalCancer Letters
Volume410
DOIs
StatePublished - Dec 1 2017

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MicroRNAs
Methylation
Histology
Non-Small Cell Lung Carcinoma
Smoking
Lung
decitabine
Neoplasms
CpG Islands
Atlases
DNA Methylation
Tumor Cell Line
Epigenomics
Small Interfering RNA
Squamous Cell Carcinoma
Lung Neoplasms
Adenocarcinoma
History
Genome
Cell Line

Keywords

  • ANK1
  • Epigenetics
  • Intronic microRNA
  • miR-486-5p
  • NSCLC

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Tessema, M., Yingling, C. M., Picchi, M. A., Wu, G., Ryba, T., Lin, Y., ... Belinsky, S. A. (2017). ANK1 Methylation regulates expression of MicroRNA-486-5p and discriminates lung tumors by histology and smoking status. Cancer Letters, 410, 191-200. https://doi.org/10.1016/j.canlet.2017.09.038

ANK1 Methylation regulates expression of MicroRNA-486-5p and discriminates lung tumors by histology and smoking status. / Tessema, Mathewos; Yingling, Christin M.; Picchi, Maria A.; Wu, Guodong; Ryba, Tyrone; Lin, Yong; Bungum, Aaron O.; Edell, Eric; Spira, Avrum; Belinsky, Steven A.

In: Cancer Letters, Vol. 410, 01.12.2017, p. 191-200.

Research output: Contribution to journalArticle

Tessema, M, Yingling, CM, Picchi, MA, Wu, G, Ryba, T, Lin, Y, Bungum, AO, Edell, E, Spira, A & Belinsky, SA 2017, 'ANK1 Methylation regulates expression of MicroRNA-486-5p and discriminates lung tumors by histology and smoking status', Cancer Letters, vol. 410, pp. 191-200. https://doi.org/10.1016/j.canlet.2017.09.038
Tessema, Mathewos ; Yingling, Christin M. ; Picchi, Maria A. ; Wu, Guodong ; Ryba, Tyrone ; Lin, Yong ; Bungum, Aaron O. ; Edell, Eric ; Spira, Avrum ; Belinsky, Steven A. / ANK1 Methylation regulates expression of MicroRNA-486-5p and discriminates lung tumors by histology and smoking status. In: Cancer Letters. 2017 ; Vol. 410. pp. 191-200.
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abstract = "The intragenic tumor-suppressor microRNA miR-486-5p is often down-regulated in non-small cell lung cancer (NSCLC) but the mechanism is unclear. This study investigated epigenetic co-regulation of miR-486-5p and its host gene ANK1. MiR-486-5p expression in lung tumors and cell lines was significantly reduced compared to normal lung (p < 0.001) and is strongly correlated with ANK1 expression. In vitro, siRNA-mediated ANK1 knockdown in NSCLC cells also reduced miR-486-5p while the DNA methylation inhibitor 5-aza-2′-deoxycytidine induced expression of both. ANK1 promoter CpG island was unmethylated in normal lung but methylated in 45{\%} (118/262) lung tumors and 55{\%} (17/31) NSCLC cell lines. After adjustment for tumor histology and smoking, methylation was significantly more prevalent in adenocarcinoma (101/200, 51{\%}) compared to squamous cell carcinoma (17/62, 27{\%}), p < 0.001; HR = 3.513 (CI: 1.818–6.788); and in smokers (73/128, 57{\%}) than never-smokers (28/72, 39{\%}), p = 0.014; HR = 2.086 (CI: 1.157–3.759). These results were independently validated using quantitative methylation data for 809 NSCLC cases from The Cancer Genome Atlas project. Together, our data indicate that aberrant ANK1 methylation is highly prevalent in lung cancer, discriminate tumors by histology and patients' smoking history, and contributes to miR-486-5p repression.",
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AU - Wu, Guodong

AU - Ryba, Tyrone

AU - Lin, Yong

AU - Bungum, Aaron O.

AU - Edell, Eric

AU - Spira, Avrum

AU - Belinsky, Steven A.

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