title: Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins.
abstract: Bromodomain and extra terminal domain (BET) proteins function as epigenetic signaling factors that associate with acetylated histones and facilitate transcription of target genes. Inhibitors targeting the activity of BET proteins have shown potent antiproliferative effects in hematological cancers through the suppression of c-MYC and downstream target genes. However, as the epigenetic landscape of a cell varies drastically depending on lineage, transcriptional coactivators such as BETs would be expected to have different targets in cancers derived from different cells of origin, and this may influence the activity and mechanism of action of BET inhibitors. To test this hypothesis, we treated a panel of lung adenocarcinoma (LAC) cell lines with the BET inhibitor JQ1 and found that a subset is acutely susceptible to BET inhibition. In contrast to blood tumors, we show that LAC cells are inhibited by JQ1 through a mechanism independent of c-MYC down-regulation. Through gene expression profiling, we discovered that the oncogenic transcription factor FOSL1 and its targets are suppressed by JQ1 in a dose-dependant manner. Knockdown of BRD4 also decreased FOSL1 levels, and inhibition of FOSL1 phenocopied the effects of JQ1 treatment, suggesting that loss of this transcription factor may be partly responsible for the cytotoxic effects of BET inhibition in LAC cells, although ectopic expression of FOSL1 alone did not rescue the phenotype. Together, these findings suggest that BET inhibitors may be useful in solid tumors and that cell-lineage-specific differences in transcriptional targets of BETs may influence the activity of inhibitors of these proteins in different cancer types.
authors.affiliation: Cancer Biology and Genetics Section, Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. william.lockwood@nih.gov
authors.forename: William W
authors.initials: WW
authors.lastname: Lockwood
authors.forename: Kreshnik
authors.initials: K
authors.lastname: Zejnullahu
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Harold
authors.initials: H
authors.lastname: Varmus
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D001381:Azepines / Q000494:pharmacology* / Q000627:therapeutic use; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D044127:Epigenesis, Genetic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000099169:Fos-Related Antigen 1; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D014230:Triazoles; D000099169:Fos-Related Antigen 1; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins