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FOXD3 is a novel tumor suppressor in lung cancer

ABSTRACT: The transcription factor forkhead box D3 (FoxD3) is a transcriptional factor which belongs to forkhead box (Fox) transcription factor family. The functions of FOXD3 in embryogenesis and in the development of neural crest cells have been clearly defined. Its tumor suppressor function hasbeen found in many types of cancer in recent years. However, the study about its roles in lung cancerdevelopment is still lacking. Our study found that deficiency of FoxD3 in lung cancer enhanced cell growth and cell invasion. RNA-sequence analysis demonstrated that loss of FoxD3 mainly affected cell cycle progression related gene expression. Knockdown of FoxD3 led to G2-M cell accumulation with up-regulation of DNA replication licensing factor MCM5 and MCM4 as well as cell cycle regulator polo-like kinase-1 (PLK1) and CDC6. Over-expression of those genesin lung cancer was associated with poor clinical outcomes of lung cancer patients. We also identified high mobility group box-1(HMGB1), Hras and Ephrin B1 gene expression increase after FoxD3 silencing which may participate in enhanced lung cancer cell invasion. Our study identifiedtumor suppressor function of FoxD3 in lung cancer andwe did the first comprehensive analysis of the genes regulated by FoxD3 for cell proliferation and invasion in lung cancer. The identified genes regulated by FoxD3 through our analysis will provide valuable information to uncover the mechanism of FoxD3 tumor suppressor function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE64513 | GEO | 2015/12/24

SECONDARY ACCESSION(S): PRJNA271162

REPOSITORIES: GEO

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FOXD3 is a novel tumor suppressor in lung cancer

Project description:The transcription factor forkhead box D3 (FoxD3) is a transcriptional factor which belongs to forkhead box (Fox) transcription factor family. The functions of FOXD3 in embryogenesis and in the development of neural crest cells have been clearly defined. Its tumor suppressor function hasbeen found in many types of cancer in recent years. However, the study about its roles in lung cancerdevelopment is still lacking. Our study found that deficiency of FoxD3 in lung cancer enhanced cell growth and cell invasion. RNA-sequence analysis demonstrated that loss of FoxD3 mainly affected cell cycle progression related gene expression. Knockdown of FoxD3 led to G2-M cell accumulation with up-regulation of DNA replication licensing factor MCM5 and MCM4 as well as cell cycle regulator polo-like kinase-1 (PLK1) and CDC6. Over-expression of those genesin lung cancer was associated with poor clinical outcomes of lung cancer patients. We also identified high mobility group box-1(HMGB1), Hras and Ephrin B1 gene expression increase after FoxD3 silencing which may participate in enhanced lung cancer cell invasion. Our study identifiedtumor suppressor function of FoxD3 in lung cancer andwe did the first comprehensive analysis of the genes regulated by FoxD3 for cell proliferation and invasion in lung cancer. The identified genes regulated by FoxD3 through our analysis will provide valuable information to uncover the mechanism of FoxD3 tumor suppressor function. Three control and three FOXD3 knockdown A549 cell lines were subjected to RNA sequencing.

2015-12-24 | E-GEOD-64513 | biostudies-arrayexpress

Genome-wide maps of chromatin binding of FOXD3

Project description:The tumor-initiating cells (TIC) are cell population that can initiate tumor, mediate drug resistance, and give rise to metastasis. FOXD3 is a forkhead box (Fox) transcription factor family that regulates the pluripotency of embryonic stem cell and tumorigenicity. However, it is unclear whether FOXD3 play any role in TIC and tumor metastasis. Here, we report that FOXD3 is down-regulated in tumor initiating cells and negatively correlated with higher histologic grades and positive lymph node metastasis. FOXD3 repress TIC expansion, cell migration, drug resistance and osteogenesis in vitro and in vivo. Mechanically, we found that FOXD3 repress a cohort of genes including SET and WDR5 and to regulate several TIC related signaling pathway. Moreover, SET and WDR5 was positively correlated with the CSC abundance and tumor progression. Besides, patients with high expression of SET and WDR5 presented a poorer overall survival. Collectively, our work defined that FOXD3-WDR5-SET axis that repress TIC accumulation and lung cancer progression.

2017-01-10 | GSE93323 | GEO

FOXD3 suppresses tumor-initiating features in lung cancer via transcriptional repression of WDR5 and SET

Project description:In this study, we demonstrated that FOXD3, acting as a repressor in the expansion of lung cancer TICs, was negatively correlated with histological grades and metastasis in lung cancer, and provided evidence that FOXD3 repressed the TIC expansion, cell invasion and drug resistance in vivo and in vitro. Global genomic RNA-Seq and Chip-seq analyses identified WDR5 and SET as the direct targets of FOXD3 in lung cancer. Inhibition of WDR5 and SET could partially rescue TIC abundance, cell invasion, osteogenesis, and gene expression signature upon depletion of FOXD3. Clinically, we revealed that FOXD3 was negatively correlated with WDR5 and SET expression, CSC abundance, and prognosis of lung cancer.

2019-12-22 | GSE92735 | GEO

Helicobacter pylori-mediated Epigenetic Dysregulation of FOXD3 Tumor-suppressive Cascade In Gastric Carcinogenesis [ChIP]

Project description:Forkhead box (Fox) proteins constitute an evolutionarily conserved family of transcriptional regulators whose deregulations lead to tumorigenesis. However, their regulation and function in gastric cancer are unknown. Promoter hypermethylation occurs during Helicobacter pylori (H pylori)-induced gastritis, but whether the deregulated genes contribute to the multi-step gastric carcinogenesis remains unclear. FOXD3 was found to be hypermethylated in a mouse model of H pylori infection and possess tumor-suppressive functions in gastric cancer cell lines. In order to characterize the direct targets of FOXD3 that confer its actions, we performed ChIP-chip in N87 gastric cancer cell line which express low level of FOXD3 in the nuclei of a sub-population of cells. Promoter hypermethylation occurs during Helicobacter pylori (H pylori)-induced gastritis, but whether the deregulated genes contribute to the multi-step gastric carcinogenesis remains unclear. We used MethylCap-microarray to identify hypermethylated genes in a mouse model of H pylori infection. human Samples: Human gastric tumor cell line, N87 was grown in RPMI1640 supplemented with 10% fetal bovine serum. ChIP assays were performed using anti-FOXD3 antibody. The immunoprecipitated-FOXD3 and -IgG DNA were used to probe the Agilent human ChIP-chip arrays. mouse Samples: Two-condition experiment, H pylori-infected vs. control gastric tissues. 2 dye-swap replicates.

2012-12-28 | E-GEOD-39490 | biostudies-arrayexpress

Helicobacter pylori-mediated Epigenetic Dysregulation of FOXD3 Tumor-suppressive Cascade In Gastric Carcinogenesis [ChIP]

2012-12-28 | GSE39490 | GEO

Homo sapiens

Project description:FOXD3 is a novel tumor suppressor in lung cancer

| PRJNA271162 | ENA

Expression data from RAW-264.7 cells transfected with empty vector and mouse FoxQ1 expression construct

Project description:Transcription factor FoxQ1 belongs to family of Fox transcription factors containing forkhead box (winged helix) domain. This family of proteins plays an important role in cell growth, proliferation, and differentiation. Expression of FoxQ1 was found in cancer cells and was associated with increased migration and invasion. Recently, elevated FoxQ1 expression was found in IL4 stimulated macrophages. We used microarrays to clarify the role of FoxQ1 in macrophages

2017-11-23 | GSE79521 | GEO

Foxd3 binding at enhancers controls developmental timing of gene expression by regulation of histone acetylation [expression array]

Project description:Transcription factor/enhancer interactions determine cell specific gene expression. Here, we followed enhancers during differentiations of embryonic stem (ESCs) to epiblast like cells (EpiLCs). There were highly dynamic changes in histone lysine 27 acetylation at enhancer sites throughout the genome. These sites were enriched for a Foxd3 binding motif, a forkhead transcription factor essential in early embryonic development. Surprisingly, Foxd3 occupied largely mutually exclusive sites in the ESCs versus EpiLCs. Foxd3 bound to nucleosome occupied regions, simultaneously evicting the histones while inhibiting full gene expression through the recruitment of histone deacetylases. Knockout of Foxd3 resulted in hyperacetylation and transcriptional upregulation of neighboring genes, many of which were further upregulated at later stages of differentiation. These data show that Foxd3 primes enhancer sites during pregastrulation by removing nucleosomes, yet suppresses neighboring histone hyperacetylation. Such a mechanism may be common to many transcription factors that prepare enhancers for later gene activation during development. Total RNA obtained Foxd3 knockout embryonic stem cells (ESCs) and epiblast-like cells (EpiLCs) (treated with 1uM tamoxifen for 36h to induce knockout) compared to wild-type controls

2015-12-08 | E-GEOD-58317 | biostudies-arrayexpress

Knockdown of FOXP1 promotes the development of lung adenocarcinoma

Project description:Lung cancer is one of the most common cancers in the world, which accounts for about 27% of all cancer deaths. However, the mechanisms underlying the pathogenesis of lung cancer cells remain largely elusive. In this study, we examined the role of the Forkhead box protein P1 (FOXP1) in lung cancer development. Our Oncomine analysis shows that FOXP1 is downregulated in lung adenocarcinoma compared with normal lung tissue. Knockdown of FOXP1 promotes the proliferation growth and invasion of PC9 and A549 cells by regulating genes of chemokine signaling molecules, including CCR1, ADCY5, GNG7, VAV3, and PLCB1. Simultaneous knockdown of CCR1 and FOXP1 attenuated FOXP1 knockdown-induced increase of lung cancer cell growth. Finally, knockdown of FOXP1 in PC9 cells promotes the tumorigenesis via CCR1 signaling in xenograft mouse model. Taken together, our data suggest that FOXP1 plays important roles in preventing lung adenocarcinoma development via suppressing chemokine signaling pathways. Novel strategies might be developed to prevent the development of lung adenocarcinoma by targeting FOXP1

2018-02-10 | GSE108500 | GEO

Foxd3 binding at enhancers controls developmental timing of gene expression by regulation of histone acetylation [ChIP-seq]

2015-12-08 | GSE58407 | GEO

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