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

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GATA2 is Epigenetically Repressed in Human and Mouse Lung Tumors and Is Not Requisite for Survival of KRAS Mutant Lung Cancer Mathewos Tessema, PhD, Christin M. Yingling, BS, Amanda M. Snider, BS, Kieu Do, BS, Daniel E. Juri, MS, Maria A. Picchi, MPH, Xiequn Zhang, MS, Yushi Liu, PhD, Shuguang Leng, PhD, Carmen S. Tellez, PhD, Steven A. Belinsky, PhD Journal of Thoracic Oncology Volume 9, Issue 6, Pages 784-793 (June 2014) DOI: 10.1097/JTO.0000000000000165 Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 GATA2 expression is significantly reduced in lung cancer and does not provide survival advantage to lung cancer cells. (A) A schematic representation of the three transcript variants of GATA2. Expression of total GATA2 in (B) tumor-normal pairs and (C) KRAS wild-type and mutant non–small-cell lung cancer (NSCLC) cell lines was compared using a TaqMan assay that detects all transcripts. Transient knockdown of GATA2 in KRAS wild-type (D) and mutant (E) NSCLC cell lines does not increase cell death (F-G). Journal of Thoracic Oncology 2014 9, 784-793DOI: (10.1097/JTO.0000000000000165) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Aberrant methylation of GATA2 is common in lung cancer and occurs early during lung carcinogenesis. (A) Combined Bisulfite Modification and Restriction Analysis assay shows GATA2 promoter CpG island is not methylated (polymerase chain reaction products are not digested into smaller fragments by BstU1 enzyme) in NHBECs and PBMCs obtained from cancer-free donors (top panel), but methylated in most KRAS wild-type and mutant non–small-cell lung cancer (NSCLC) cell lines (bottom panel). (B) The degree of methylation across the GATA2 promoter could be estimated based on the proportion of undigested and digested fragments. Top panel: Among the NSCLC cell lines evaluated, GATA2 was not methylated in SKMES1 (0%), partially methylated in SW900 (~25%), HCC4006 (~50%), and H1975 (~75%), and completely methylated (100%) in H23 and the remaining cell lines as also shown in the bottom panel of (A). Bottom panel: the higher proportion of undigested bands in the BstU1+ lanes in the DAC than trichostatin A and Vehicle (Cont) treated KRAS wild-type (H1838) and mutant (H358) NSCLC cell lines indicates demethylation of GATA2 by DAC treatment. (C) The Combined Bisulfite Modification and Restriction Analysis primers that amplify bisulfite modified GATA2 promoter CpG island regardless of its methylation were used as modified DNA specific PCR (ModSP). Methylation Specific PCR assays using primers that specifically amplify only the methylated promoter show that GATA2 is unmethylated in NHBECs and HBECs (no band). However, methylation was detected in HBEC2 after 12 weeks of exposure to the tobacco carcinogens methylnitrosourea and benzo(a)pyrene-diolepoxide and in the transformed HBEC1, 2, and 14 that were exposed to these carcinogens for 12 weeks and further selected for growth in soft agar. Quantitative methylation data from HM450K arrays show increased methylation of eight probes located within the GATA2 promoter CpG island during transformation of (D) HBEC2 and (E) HBEC14. These eight probes were not methylated in normal lung but aberrantly hypermethylated in nearly all lung tumors. Journal of Thoracic Oncology 2014 9, 784-793DOI: (10.1097/JTO.0000000000000165) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Epigenetic repression of GATA2 in early lung carcinogenesis is mediated by chromatin modification and progresses to a more stable repression by adding cytosine-DNA methylation upon transformation. (A) GATA2 expression responds better to the histone deacetylase inhibitor trichostatin A, while transformed HBECs (B), KRAS wild-type (C) and mutant (D) non–small-cell lung cancer (NSCLC) cell lines show better response to the DNA methyltransferases inhibitor DAC. (E) Chromatin marks for transcriptional repression were increased during transformation of HBEC2 and the highest repression marks were seen in NSCLC cell lines, Calu6 (KRAS mutant) and H1975 (KRAS wild-type). Journal of Thoracic Oncology 2014 9, 784-793DOI: (10.1097/JTO.0000000000000165) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions