Tumor progression and chromatin landscape of lung cancer are regulated by the lineage factor GATA6.
Anna Arnal-EstapeWesley L CaiAlexandra E AlbertMinghui ZhaoLaura E StevensFrancesc López-GiráldezKiran D PatelSiddhartha TyagiEarlene M SchmittThomas F WestbrookDon X NguyenPublished in: Oncogene (2020)
Lineage selective transcription factors (TFs) are important regulators of tumorigenesis, but their biological functions are often context dependent with undefined epigenetic mechanisms of action. In this study, we uncover a conditional role for the endodermal and pulmonary specifying TF GATA6 in lung adenocarcinoma (LUAD) progression. Impairing Gata6 in genetically engineered mouse models reduces the proliferation and increases the differentiation of Kras mutant LUAD tumors. These effects are influenced by the epithelial cell type that is targeted for transformation and genetic context of Kras-mediated tumor initiation. In LUAD cells derived from surfactant protein C expressing progenitors, we identify multiple genomic loci that are bound by GATA6. Moreover, suppression of Gata6 in these cells significantly alters chromatin accessibility, particularly at distal enhancer elements. Analogous to its paradoxical activity in lung development, GATA6 expression fluctuates during different stages of LUAD progression and can epigenetically control diverse transcriptional programs associated with bone morphogenetic protein signaling, alveolar specification, and tumor suppression. These findings reveal how GATA6 can modulate the chromatin landscape of lung cancer cells to control their proliferation and divergent lineage dependencies during tumor progression.
Keyphrases
- transcription factor
- single cell
- dna binding
- poor prognosis
- induced apoptosis
- genome wide
- gene expression
- genome wide identification
- signaling pathway
- wild type
- cell cycle arrest
- dna methylation
- public health
- binding protein
- long non coding rna
- pulmonary hypertension
- mouse model
- dna damage
- copy number
- cell fate
- oxidative stress
- cell death