GATA6 induces cell senescence to exerts lung cancer suppressive function and denotes a therapeutic opportunity for GATA6 deficient lung cancer patients
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ABSTRACT:
PROVIDER: PRJNA614904 | ENA |
REPOSITORIES: ENA
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Project description:Lung cancer is the world-wide leading cause of cancer related deaths. Tumor suppressor genes (TSGs) play a critical role in restricting tumorigenesis and impact the therapeutic effect of various treatments. However, TSGs remain to be systemically determined in lung cancer. Here we identified GATA6 as a potent lung cancer TSG. GATA6 inhibited lung cancer cell growth in vitro and tumorigenesis in vivo. Mechanistically, GATA6 upregulated p53 expression to transcribe p21 mRNA while inhibited Akt activation to stabilize p21 protein, thus inducing lung cancer cell senescence. Furthermore, we showed that ectopic expression of GATA6 led to dramatic shrinkage of established lung tumor in vivo
2020-03-25 | GSE147447 | GEO
Project description:Epithelial organs including the lung are known to possess regenerative abilities through activation of endogenous stem cell populations but the molecular pathways regulating stem cell expansion and regeneration are not well understood. Here we show that Gata6 regulates the temporal appearance and number of bronchioalveolar stem cells (BASCs) in the lung leading to the precocious appearance of BASCs and concurrent loss in epithelial differentiation in Gata6 null lung epithelium. This expansion of BASCs is the result of a dramatic increase in canonical Wnt signaling in lung epithelium upon loss of Gata6. Expression of the non-canonical Wnt receptor Fzd2 is down-regulated in Gata6 mutants and increased Fzd2 or decreased β-catenin expression rescues, in part, the lung epithelial defects in Gata6 mutants. During lung epithelial regeneration, we show that canonical Wnt signaling is activated in the niche containing BASCs and forced activation of Wnt signaling leads to a dramatic increase in BASC numbers. Moreover, Gata6 is required for proper lung epithelial regeneration and postnatal loss of Gata6 leads to increased BASC expansion and decreased differentiation. Together, these data demonstrate that Gata6 regulated Wnt signaling controls the balance between stem/progenitor expansion and epithelial differentiation required for both lung development and regeneration. Keywords: gene targets in knockout mouse model
2008-04-15 | GSE11165 | GEO
Project description:Epithelial organs including the lung are known to possess regenerative abilities through activation of endogenous stem cell populations but the molecular pathways regulating stem cell expansion and regeneration are not well understood. Here we show that Gata6 regulates the temporal appearance and number of bronchioalveolar stem cells (BASCs) in the lung leading to the precocious appearance of BASCs and concurrent loss in epithelial differentiation in Gata6 null lung epithelium. This expansion of BASCs is the result of a dramatic increase in canonical Wnt signaling in lung epithelium upon loss of Gata6. Expression of the non-canonical Wnt receptor Fzd2 is down-regulated in Gata6 mutants and increased Fzd2 or decreased β-catenin expression rescues, in part, the lung epithelial defects in Gata6 mutants. During lung epithelial regeneration, we show that canonical Wnt signaling is activated in the niche containing BASCs and forced activation of Wnt signaling leads to a dramatic increase in BASC numbers. Moreover, Gata6 is required for proper lung epithelial regeneration and postnatal loss of Gata6 leads to increased BASC expansion and decreased differentiation. Together, these data demonstrate that Gata6 regulated Wnt signaling controls the balance between stem/progenitor expansion and epithelial differentiation required for both lung development and regeneration. Experiment Overall Design: 3 replicates of each condition-wild-type and GATA6 null tissue. 6 total samples.
2008-06-11 | E-GEOD-11165 | biostudies-arrayexpress
Project description:Lineage selective transcription factors (TFs) are important regulators of tumorigenesis, but their biological functions are often context dependent and their epigenetic mechanisms of action undefined. In this study, we uncover a conditional role for the endodermal and pulmonary specifying TF GATA6 during the initiation and progression of Kras mutant lung adenocarcinoma (LUAD). Inhibition of Gata6 in genetically engineered mouse models dampens the proliferation and increases the differentiation of LUAD tumors. These effects are influenced in part by the epithelial cell type that is targeted for transformation. In lung cancer 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 the developing lungs, GATA6 expression fluctuates during different stages of LUAD progression and can control diverse lineage gene expression networks associated with cell proliferation, alveolar specification, BMP signaling, and epithelial plasticity. These findings demonstrate how GATA6 can broadly modulate the epigenome of lung tumor cells, which in turn may potentiate its divergent functions during cancer progression
2020-03-05 | GSE124601 | GEO
Project description:Lineage selective transcription factors (TFs) are important regulators of tumorigenesis, but their biological functions are often context dependent and their epigenetic mechanisms of action undefined. In this study, we uncover a conditional role for the endodermal and pulmonary specifying TF GATA6 during the initiation and progression of Kras mutant lung adenocarcinoma (LUAD). Inhibition of Gata6 in genetically engineered mouse models dampens the proliferation and increases the differentiation of LUAD tumors. These effects are influenced in part by the epithelial cell type that is targeted for transformation. In lung cancer 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 the developing lungs, GATA6 expression fluctuates during different stages of LUAD progression and can control diverse lineage gene expression networks associated with cell proliferation, alveolar specification, BMP signaling, and epithelial plasticity. These findings demonstrate how GATA6 can broadly modulate the epigenome of lung tumor cells, which in turn may potentiate its divergent functions during cancer progression
2020-03-05 | GSE124603 | GEO
Project description:Lineage selective transcription factors (TFs) are important regulators of tumorigenesis, but their biological functions are often context dependent and their epigenetic mechanisms of action undefined. In this study, we uncover a conditional role for the endodermal and pulmonary specifying TF GATA6 during the initiation and progression of Kras mutant lung adenocarcinoma (LUAD). Inhibition of Gata6 in genetically engineered mouse models dampens the proliferation and increases the differentiation of LUAD tumors. These effects are influenced in part by the epithelial cell type that is targeted for transformation. In lung cancer 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 the developing lungs, GATA6 expression fluctuates during different stages of LUAD progression and can control diverse lineage gene expression networks associated with cell proliferation, alveolar specification, BMP signaling, and epithelial plasticity. These findings demonstrate how GATA6 can broadly modulate the epigenome of lung tumor cells, which in turn may potentiate its divergent functions during cancer progression
2020-03-05 | GSE124602 | GEO
Project description:Gata6 regulates lung epithelial stem cell development and airway regeneration. Here, the expression profile of microRNA was investigated when Gata6 was depleted during lung development.
2011-03-01 | GSE25874 | GEO
Project description:Gata6 regulates lung epithelial stem cell development and airway regeneration. Here, the expression profile of microRNA was investigated when Gata6 was depleted during lung development. Analysis used total RNA from Sftpc-rtTA:tetO-cre lungs at E14.5 as control samples (WT) for comparison to the experimental samples of total RNA from Gata6flox/flox: Sftpc-rtTA: tetO-Cre mutant lungs at E14.5.
2011-03-01 | E-GEOD-25874 | biostudies-arrayexpress
Project description:Molecular programs that mediate normal cell differentiation are required for oncogenesis and tumor cell survival in certain types of cancers. How cell lineage restricted genes specifically influence metastatic progression is poorly defined. In lung cancers, we uncovered an alveolar cell-selective transcriptional program that preferentially correlates with lung adenocarcinoma metastasis. This program is required for epithelial specification in the distal airways and is partially regulated by the lineage transcription factors GATA6 and HOPX. These factors cooperatively restrain the metastatic competence of adenocarcinoma cells, without affecting their survival, through the modulation of alveologenic and invasogenic target genes. Thus, GATA6 and HOPX are critical nodes in a lineage-selective pathway that directly links alveolar cell fate with metastasis suppresion in the lung adenocarcinoma subtype. mRNA profiles of human lung Adenocarcinoma PC9 cell lines infected with lentivirus harboring shRNA of control (Arab1) and shRNA of both GATA6 and HOPX were generated by deep sequencing, in triplicate, using Illumina HiSeq2000.
2013-06-10 | E-GEOD-39121 | biostudies-arrayexpress
Project description: Not available
| S-EPMC7304445 | biostudies-literature