GATA2 is epigenetically repressed in human and mouse lung tumors and is not requisite for survival of KRAS mutant lung cancer.

ABSTRACT: 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.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.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.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.

SUBMITTER: Tessema M 

PROVIDER: S-EPMC4132640 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature