Skip Navigation LinksHome > June 2014 - Volume 9 - Issue 6 > GATA2 is Epigenetically Repressed in Human and Mouse Lung Tu...
Journal of Thoracic Oncology:
doi: 10.1097/JTO.0000000000000165
Original Articles

GATA2 is Epigenetically Repressed in Human and Mouse Lung Tumors and Is Not Requisite for Survival of KRAS Mutant Lung Cancer

Tessema, Mathewos PhD; Yingling, Christin M. BS; Snider, Amanda M. BS; Do, Kieu BS; Juri, Daniel E. MS; Picchi, Maria A. MPH; Zhang, Xiequn MS; Liu, Yushi PhD; Leng, Shuguang PhD; Tellez, Carmen S. PhD; Belinsky, Steven A. PhD

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Abstract

Introduction:

GATA2 was recently described as a critical survival factor and therapeutic target for KRAS mutant non–small-cell lung cancer (NSCLC). However, whether this role is affected by epigenetic repression of GATA2 in lung cancer is unclear.

Methods:

GATA2 expression and promoter CpG island methylation were evaluated using human and mouse NSCLC cell lines and tumor-normal pairs. In vitro assays were used to study GATA2 repression on cell survival and during tobacco carcinogen-induced transformation.

Results:

GATA2 expression in KRAS wild-type (n = 15) and mutant (n = 10) NSCLC cell lines and primary lung tumors (n = 24) was significantly lower, 1.3- to 33.6-fold (p = 2.2 × 109), compared with corresponding normal lung. GATA2 promoter was unmethylated in normal lung (0 of 10) but frequently methylated in lung tumors (96%, 159 of 165) and NSCLC cell lines (97%, 30 of 31). This highly prevalent aberrant methylation was independently validated using The Cancer Genome Atlas data for 369 NSCLC tumor-normal pairs. In vitro studies using an established carcinogen-induced premalignancy model revealed that GATA2 expression was initially repressed by chromatin remodeling followed by cytosine methylation during transformation. Similarly, expression of GATA2 in NNK-induced mouse lung tumors (n = 6) and cell lines (n = 5) was fivefold and 100-fold lower, respectively, than normal mouse lung. Finally, siRNA-mediated knockdown of GATA2 in KRAS mutant (human [n = 4] and murine [n = 5]) and wild-type (human [n = 4]) NSCLC cell lines showed that further reduction of expression (up to 95%) does not induce cell death.

Conclusion:

GATA2 is epigenetically repressed in human and mouse lung tumors and its further inhibition is not a valid therapeutic strategy for KRAS mutant lung cancer.

Copyright © 2014 by the International Association for the Study of Lung Cancer

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