<scp>GATA</scp>6‐positive lung adenocarcinomas are associated with invasive mucinous adenocarcinoma morphology, hepatocyte nuclear factor 4α expression, and <i><scp>KRAS</scp></i> mutations

Nakajima, N.; Yoshizawa, Akihiko; Nakajima, Takahito; Hirata, Masahiro; Furuhata, Ayako; Saito, Shinji; Rokutan‐Kurata, Mariyo; Sonobe, Makoto; Menju, Toshi; Miyamoto, Ei; Chen‐Yoshikawa, Toyofumi F.; Haga, Hironori

doi:10.1111/his.13500

Cited by 20 publications

(20 citation statements)

References 42 publications

(98 reference statements)

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“…Aberrant levels of NKX2-1 in particular may target newly open chromatin regions in KPG tumor cells to activate de-novo tumor suppressive gene networks. Paradoxically, in late stage human LUAD, GATA6 is repressed along with other lineage TFs such as NKX2-1 and HOPX [12,13], and the cooperative reduction of these factors promotes metastasis in experimental models [14,39]. GATA6 is also rarely mutated in human lung cancers.…”

Section: Discussionmentioning

confidence: 99%

“…We and others have previously identified different molecular subtypes of LUAD, which have distinct developmental gene expression profiles [14,27,28]. High GATA6 expression in particular may be a context-dependent marker of KRAS mutant tumors that express markers of the distal airways [12] and committed alveolar cells (alveolarlike or alveolar-high tumors) [14,29]. NKX2-1 and HOPX can inhibit LUAD progression [14,30], and their expression was partially inversely correlated with GATA6 in "alveolarhigh" tumors but less so in other LUAD subtypes (Supplementary Fig.…”

Section: Suppressing Gata6 Reprograms Chromatin At Distal Enhancersmentioning

confidence: 94%

“…Malignancies from endodermal tissues frequently harbor KRAS mutations [15], and GATA6 expression correlates with KRAS mutations in human lung cancers [12]. In the lox-stop-lox Kras LSL-G12D genetically engineered mouse model (GEMM) (referred to herein as K), low-grade adenomas, and lung adenocarcinoma (LUAD) arise by expression of a mutant Kras allele (Kras LSL-G12D ) in the proximal-distal airways [16].…”

Section: Gata6 Regulates Tumor Grade and Proliferation Of Nsclcmentioning

confidence: 99%

“…In human lung cancers, GATA6 is rarely mutated, but its expression is increased in early stage non small cell lung cancer (NSCLC) relative to normal tissue and may correlate with tumor promoting genes [10,11]. However, GATA6 is decreased in high-grade NSCLC [12,13], and this reduction can enhance metastatic competence [14]. The mechanisms of GATA6's paradoxical functions during malignant transformation in the lungs are unknown and may reflect the conditional requirement for lineage TFs during various stages of lung development.…”

Section: Introductionmentioning

confidence: 99%

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Tumor progression and chromatin landscape of lung cancer are regulated by the lineage factor GATA6

et al. 2020

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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 Krasmediated 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.

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Section: Discussionmentioning

confidence: 99%

Section: Suppressing Gata6 Reprograms Chromatin At Distal Enhancersmentioning

confidence: 94%

Section: Gata6 Regulates Tumor Grade and Proliferation Of Nsclcmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tumor progression and chromatin landscape of lung cancer are regulated by the lineage factor GATA6

et al. 2020

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“…An illustrative example is the opposing effects of HNF4α on fibrosis in cardiac and liver tissue. In cardiac tissue, HNF4α is downstream of AMPK, and upregulation of expression was seen in an angiotensin II-induced cardiac fibrosis mouse model[82]. Metformin inhibition or knockout of AMPK reduced cardiac fibrosis, in part by preventing increased HNF4α expression.…”

Section: Hnf4alpha Activity As a Therapeutic Potentialmentioning

confidence: 99%

Role of hepatocyte nuclear factor 4-alpha in gastrointestinal and liver diseases

Yeh

Daoud

2019

WJG

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Hepatocyte nuclear factor 4-alpha (HNF4α) is a highly conserved member of nuclear receptor superfamily of ligand-dependent transcription factors that is expressed in liver and gastrointestinal organs (pancreas, stomach, and intestine). In liver, HNF4α is best known for its role as a master regulator of liver-specific gene expression and essential for adult and fetal liver function. Dysregulation of HNF4α expression has been associated with many human diseases such as ulcerative colitis, colon cancer, maturity-onset diabetes of the young, liver cirrhosis, and hepatocellular carcinoma. However, the precise role of HNF4α in the etiology of these human pathogenesis is not well understood. Limited information is known about the role of HNF4α isoforms in liver and gastrointestinal disease progression. There is, therefore, a critical need to know how disruption of the expression of these isoforms may impact on disease progression and phenotypes. In this review, we will update our current understanding on the role of HNF4α in human liver and gastrointestinal diseases. We further provide additional information on possible use of HNF4α as a target for potential therapeutic approaches.

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PLAU, transcriptionally negatively regulated by GATA6, promotes lung squamous carcinoma cell proliferation and migration

Guo,

Wang,

Huang

et al. 2024

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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GATA6‐positive lung adenocarcinomas are associated with invasive mucinous adenocarcinoma morphology, hepatocyte nuclear factor 4α expression, and KRAS mutations

Abstract: These findings suggest that GATA6 might interact with HNF4α and contribute to the development of mucinous-type LAs.

Cited by 20 publications

References 42 publications

Tumor progression and chromatin landscape of lung cancer are regulated by the lineage factor GATA6

Tumor progression and chromatin landscape of lung cancer are regulated by the lineage factor GATA6

Role of hepatocyte nuclear factor 4-alpha in gastrointestinal and liver diseases

PLAU, transcriptionally negatively regulated by GATA6, promotes lung squamous carcinoma cell proliferation and migration

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