title: GATA2 is epigenetically repressed in human and mouse lung tumors and is not requisite for survival of KRAS mutant lung cancer.
abstract: BACKGROUND
  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 × 10(9)), 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM.
authors.forename: Mathewos
authors.initials: M
authors.lastname: Tessema
authors.forename: Christin M
authors.initials: CM
authors.lastname: Yingling
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Snider
authors.forename: Kieu
authors.initials: K
authors.lastname: Do
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Juri
authors.forename: Maria A
authors.initials: MA
authors.lastname: Picchi
authors.forename: Xiequn
authors.initials: X
authors.lastname: Zhang
authors.forename: Yushi
authors.initials: Y
authors.lastname: Liu
authors.forename: Shuguang
authors.initials: S
authors.lastname: Leng
authors.forename: Carmen S
authors.initials: CS
authors.lastname: Tellez
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000139:chemically induced / Q000235:genetics*; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly; D018899:CpG Islands / Q000235:genetics; D003596:Cytosine / Q000378:metabolism; D019175:DNA Methylation; D063185:Epigenetic Repression; D050989:GATA2 Transcription Factor / Q000235:genetics*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics*; D051379:Mice; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D003596:Cytosine; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins