Genome-Wide Analysis of the FOXA1 Transcriptional Network Identifies Novel Protein-Coding and Long Noncoding RNA Targets in Colorectal Cancer Cells

Lazar, Sarah B.; Li, Xiao Ling; Grammatikakis, Ioannis; Muys, Bruna Rodrigues; Dangelmaier, Emily A.; Redon, Christophe E.; Jang, Sang‐Min; Walker, Robert L.; Tang, Wei; Ambs, Stefan; Harris, Curtis C.; Meltzer, Paul S.; Aladjem, Mirit I.; Lal, Ashish

doi:10.1128/mcb.00224-20

Cited by 15 publications

(10 citation statements)

References 75 publications

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“…3 A ). While a reduced function of FOXA1 is involved in the progression and metastasis of cancers derived from digestive organs ( 88 , 89 , 90 ), some studies suggest its role in the promotion of metastasis in pancreatic, breast, and prostate cancers ( 91 , 92 , 93 , 94 ). Therefore, the outcome of the BACH1–FOXA1 axis may be dependent on the cell context.…”

Section: Functions Of Bach1 In Cancer Metastasismentioning

confidence: 99%

The transcription factor BACH1 at the crossroads of cancer biology: From epithelial–mesenchymal transition to ferroptosis

Igarashi

Nishizawa

Saiki

et al. 2021

Journal of Biological Chemistry

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The progression of cancer involves not only the gradual evolution of cells by mutations in DNA but also alterations in the gene expression induced by those mutations and input from the surrounding microenvironment. Such alterations contribute to cancer cells' abilities to reprogram metabolic pathways and undergo epithelial-to-mesenchymal transition (EMT), which facilitate the survival of cancer cells and their metastasis to other organs. Recently, BTB and CNC homology 1 (BACH1), a heme-regulated transcription factor that represses genes involved in iron and heme metabolism in normal cells, was shown to shape the metabolism and metastatic potential of cancer cells. The growing list of BACH1 target genes in cancer cells reveals that BACH1 promotes metastasis by regulating various sets of genes beyond iron metabolism. BACH1 represses the expression of genes that mediate cell–cell adhesion and oxidative phosphorylation but activates the expression of genes required for glycolysis, cell motility, and matrix protein degradation. Furthermore, BACH1 represses FOXA1 gene encoding an activator of epithelial genes and activates SNAI2 encoding a repressor of epithelial genes, forming a feedforward loop of EMT. By synthesizing these observations, we propose a “two-faced BACH1 model”, which accounts for the dynamic switching between metastasis and stress resistance along with cancer progression. We discuss here the possibility that BACH1-mediated promotion of cancer also brings increased sensitivity to iron-dependent cell death (ferroptosis) through crosstalk of BACH1 target genes, imposing programmed vulnerability upon cancer cells. We also discuss the future directions of this field, including the dynamics and plasticity of EMT.

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Section: Functions Of Bach1 In Cancer Metastasismentioning

confidence: 99%

The transcription factor BACH1 at the crossroads of cancer biology: From epithelial–mesenchymal transition to ferroptosis

Igarashi

Nishizawa

Saiki

et al. 2021

Journal of Biological Chemistry

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“…CDKN2B [772], hsa-mir-146a [768] and ESR1 [773] have been thought of as a specific and exclusive biomarkers for ulcerative colitis. CDKN2B [774], hsa-mir-25-5p [775], hsa-mir-146a [768], hsa-mir-148a-3p [776], NFYA (Nuclear Transcription Factor Y Subunit Alpha) [777], FOXA1 [778], ESR1 [779], ARID3A [780], PRDM1 [781], GATA2 [782], HOXA5 [783] and BRCA1 [784] were significantly associated in colorectal cancer. Theses colorectal cancer biomarkers might plays important regulatory roles in CD.…”

Section: Discussionmentioning

confidence: 99%

Identification of hub genes and key pathways in pediatric Crohn’s disease using next generation sequencing and bioinformatics analysis

Vastrad¹,

Vastrad²

2022

Preprint

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Pediatric Crohn's Disease (CD) also known as inflammatory bowel diseases, affects millions of people all over the world. The aim of this investigation is to identify the key genes in CD and uncover their potential functions. We downloaded the next generation sequencing (NGS) dataset GSE73374 from the Gene Expression Omnibus (GEO) database. The NGS dataset GSE73374 was used to screen differentially expressed genes (DEGs) between samples from patients with CD and healthy controls. Gene ontology (GO) and REACTOME pathway enrichment analyses were applied for the DEGs. Subsequently, a protein - protein interaction (PPI) network, modules, miRNA- hub gene regulatory network and TF - hub gene regulatory network were constructed to identify hub genes, miRNAs and TFs. Receiver operating characteristic curve (ROC) analysis was applied to validate the hub genes. A total of 957 DEGs were identified, including 478 up regulated genes and 479 down regulated genes. GO and REACTOME results suggested that several Go terms and pathways are involved in response to stimulus, extracellular region, signaling receptor binding, small molecule metabolic process, membrane, transporter activity, immune system and biological oxidations. The top centrality hub genes MDFI, MNDA, FBXO6, TFRC, STAT1, DPP4, MME, SLC39A4, APOA1 and TMEM25 were screened out as the critical genes among the DEGs from the PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network. This investigation identified key genes and signal pathways, which might help us improve our understanding of the molecular mechanisms of CD and identify some novel therapeutic targets for CD.

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“…Additionally, FOXA1 was significantly down-regulated in CRC tumors (Figure 1F) and knockdown of FOXA1 in LS180 and SW1222 significantly decreased FORCP levels (Figure 1G and Figure 1-figure supplement 3C-E and Figure 1-figure supplement 3-source data 1). By performing FOXA1 ChIP-seq [39] followed by ChIP-qPCR, we identified and validated FOXA1 binding to the FORCP locus (Figure 1H and I). These data suggest that FOXA1 enhances FORCP transcription in the welldifferentiated CRC cells.…”

Section: Forcp Is Transcriptionally Activated By Foxa1 In Well-differentiated Crc Cellsmentioning

confidence: 96%

A small protein encoded by a putative lncRNA regulates apoptosis and tumorigenicity in human colorectal cancer cells

Tang²,

Das

et al. 2020

eLife

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Long noncoding RNAs (lncRNAs) are often associated with polysomes, indicating coding potential. However, only a handful of endogenous proteins encoded by putative lncRNAs have been identified and assigned a function. Here, we report the discovery of a putative gastrointestinal tract-specific lncRNA (LINC00675) that is regulated by the pioneer transcription factor FOXA1 and encodes a conserved small protein of 79 amino acids which we termed FORCP (FOXA1-Regulated Conserved Small Protein). FORCP transcript is undetectable in most cell types but is abundant in well-differentiated colorectal cancer (CRC) cells where it functions to inhibit proliferation, clonogenicity and tumorigenesis. The epitope-tagged and endogenous FORCP protein predominantly localizes to the endoplasmic reticulum (ER). In response to ER stress, FORCP depletion results in decreased apoptosis. Our findings on the initial characterization of FORCP demonstrate that FORCP is a novel, conserved small protein encoded by a mis-annotated lncRNA that regulates apoptosis and tumorigenicity in well-differentiated CRC cells.

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Genome-Wide Analysis of the FOXA1 Transcriptional Network Identifies Novel Protein-Coding and Long Noncoding RNA Targets in Colorectal Cancer Cells

Cited by 15 publications

References 75 publications

The transcription factor BACH1 at the crossroads of cancer biology: From epithelial–mesenchymal transition to ferroptosis

The transcription factor BACH1 at the crossroads of cancer biology: From epithelial–mesenchymal transition to ferroptosis

Identification of hub genes and key pathways in pediatric Crohn’s disease using next generation sequencing and bioinformatics analysis

A small protein encoded by a putative lncRNA regulates apoptosis and tumorigenicity in human colorectal cancer cells

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