Multiple roles and regulatory mechanisms of the transcription factor GATA6 in human cancers

Sun, Zhaoqing; Yan, Bo

doi:10.1111/cge.13630

Cited by 25 publications

(20 citation statements)

References 109 publications

(208 reference statements)

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“…GATA6 is one of six members of the mammalian GATA family of transcriptional regulators and is expressed in various normal tissues derived from the mesoderm and endoderm (Almalki and Agrawal, 2016). An oncogenic role for GATA6 has been proposed in various cancers including pancreatic cancer where its knockdown reduced cell proliferation and cell-cycle progression (Sun and Yan, 2020). In line with these observations, we show that the loss of GATA6 impairs proliferation of mesenchymal-like cells.…”

Section: Discussionsupporting

confidence: 89%

TFIIH kinase CDK7 antagonizes phenotype switching and emergence of drug tolerance in melanoma

Berico

Cigrang

Braun

et al. 2020

Preprint

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Melanoma cells switch back-and-forth between phenotypes of proliferation and invasion in response to changing microenvironment, driving metastatic progression. We show that inhibition of the TFIIH kinase CDK7 (CDK7i) results in a melanocytic to mesenchymal phenotype switching and acquisition of targeted therapy tolerance. We identify a gene expression program controlled by the transcription factor GATA6, which participates in drug tolerance in mesenchymal-like cells and which is antagonized by CDK7 in melanocytic-like cells. This program emerges concomitantly with loss of melanocyte lineage-specific MITF protein following CDK7i. By dissecting the underlying mechanism, we observe that CDK7 accumulates at the super-enhancer regulating MITF to drive its expression. MITF itself binds to a intronic region of GATA6 to transcriptionally repress it. This molecular cascade antagonizes expression of the GATA6 regulon that only emerges in MITF-low cells of metastatic melanoma. Our work reveals a role for CDK7 in counteracting phenotype switching and activation of a gene expression program mediating multidrug tolerance in melanoma cells.

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Section: Discussionsupporting

confidence: 89%

TFIIH kinase CDK7 antagonizes phenotype switching and emergence of drug tolerance in melanoma

Berico

Cigrang

Braun

et al. 2020

Preprint

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“…The transcription factor GATA6 is widely associated with tumorigenesis [139], including an oncogenic role in CTCL [140]. In SS T cells, GATA6 is overexpressed and directly induces expression of CD137L, which promotes proliferation, survival and migration of SS T cells and CTCL cell lines [22,110,140].…”

Section: New and Promising Ss-unique Biomarker Genesmentioning

confidence: 99%

Gene Expression Comparison between Sézary Syndrome and Lymphocytic-Variant Hypereosinophilic Syndrome Refines Biomarkers for Sézary Syndrome

Moerman-Herzog

Mehdi

Wong

2020

Cells

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Sézary syndrome (SS), an aggressive cutaneous T-cell lymphoma (CTCL) with poor prognosis, is characterized by the clinical hallmarks of circulating malignant T cells, erythroderma and lymphadenopathy. However, highly variable clinical skin manifestations and similarities with benign mimickers can lead to significant diagnostic delay and inappropriate therapy that can lead to disease progression and mortality. SS has been the focus of numerous transcriptomic-profiling studies to identify sensitive and specific diagnostic and prognostic biomarkers. Benign inflammatory disease controls (e.g., psoriasis, atopic dermatitis) have served to identify chronic inflammatory phenotypes in gene expression profiles, but provide limited insight into the lymphoproliferative and oncogenic roles of abnormal gene expression in SS. This perspective was recently clarified by a transcriptome meta-analysis comparing SS and lymphocytic-variant hypereosinophilic syndrome, a benign yet often clonal T-cell lymphoproliferation, with clinical features similar to SS. Here we review the rationale for selecting lymphocytic-variant hypereosinophilic syndrome (L-HES) as a disease control for SS, and discuss differentially expressed genes that may distinguish benign from malignant lymphoproliferative phenotypes, including additional context from prior gene expression studies to improve understanding of genes important in SS.

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“…In addition to higher expression in fetal heart and lung, GATA6 gene can also be expressed in adult heart, pancreas, ovary, lung, liver, central nervous system, adrenal, and VSMCs (Morrisey et al, 1996; Suzuki et al, 1996; Pikkarainen et al, 2004). Decreased or elevated expression of the GATA6 gene has been reported to be associated with many cardiovascular diseases in humans, such as CHD, arrhythmia, cardiomyopathy, and neonatal and adult diabetes (Sun and Yan, 2019). The two GATA6 gene DSVs identified in our study are located at -1,075 and -1,028 bp upstream of the transcription start site, which may affect the interaction with other transcription factors, enhancing their transcriptional activity.…”

Section: Discussionmentioning

confidence: 99%

Genetic and Functional Variants Analysis of the GATA6 Gene Promoter in Acute Myocardial Infarction

et al. 2019

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Background: Acute myocardial infarction (AMI) which is a specific type of coronary artery disease (CAD), is caused by the combination of genetic factors and acquired environment. Although some common genetic variations have been recorded to contribute to the development of CAD and AMI, more genetic factors and potential molecular mechanisms remain largely unknown. The GATA6 gene is expressed in the heart during embryogenesis and is also detected in vascular smooth muscle cells (VSMCs), different human primary endothelial cells (ECs), and vascular ECs in mice. To date, no studies have directly linked GATA6 gene with regulation of the CAD. Methods: In this study, we used a case-control study to investigate and analyze the genetic variations and functional variations of the GATA6 gene promoter region in AMI patients and controls. A variety of statistical analysis methods were utilized to analyze the association of single nucleotide polymorphisms (SNPs) with AMI. Functional analysis of DNA sequence variants (DSVs) was performed using a dual luciferase reporter assay. In vitro, electrophoretic mobility shift assay (EMSA) was selected to examine DNA-protein interactions. Results: A total of 705 subjects were enrolled in the study. Ten DSVs were found in AMI patients (n = 352) and controls (n = 353), including seven SNPs. One novel heterozygous DSV, (g.22168409 A > G), and two SNPs, [g.22168362 C > A(rs1416421760) and g.22168521 G > T(rs1445501474)], were reported in three AMI patients, which were not found in controls. The relevant statistical analysis, including allele and genotype frequencies between AMI patients and controls, five genetic models, linkage disequilibrium (LD) and haplotype analysis, and SNP–SNP interactions, suggested no statistical significance (P > 0.05). The transcriptional activity of GATA6 gene promoter was significantly increased by the DSV (g.22168409 A > G) and SNP [g.22168362 C > A(rs1416421760)]. The EMSA revealed that the DSV (g.22168409 A > G) and SNP [g.22168362 C > A(rs1416421760)] evidently influenced the binding of transcription factors. Conclusion: In conclusion, the DSV (g.22168409 A > G) and SNP [g.22168362 C > A(rs1416421760)] may increase GATA6 levels in both HEK-293 and H9c2 cell lines by affecting the binding of transcription factors. Whether the two variants identified in the GATA6 gene promoter can promote the development and progression of human AMI by altering GATA6 levels still requires further studies to verify.

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Multiple roles and regulatory mechanisms of the transcription factor GATA6 in human cancers

Cited by 25 publications

References 109 publications

TFIIH kinase CDK7 antagonizes phenotype switching and emergence of drug tolerance in melanoma

TFIIH kinase CDK7 antagonizes phenotype switching and emergence of drug tolerance in melanoma

Gene Expression Comparison between Sézary Syndrome and Lymphocytic-Variant Hypereosinophilic Syndrome Refines Biomarkers for Sézary Syndrome

Genetic and Functional Variants Analysis of the GATA6 Gene Promoter in Acute Myocardial Infarction

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