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DeltaNp63 silencing, DNA methylation shifts and epithelial mesenchymal transition resulted from TAp63 genome editing in squamous cell carcinoma [microarray]

ABSTRACT: DeltaNp63 silencing, DNA methylation shifts and epithelial mesenchymal transition resulted from TAp63 genome editing in squamous cell carcinoma [microarray]

PROVIDER: PRJNA983830 | ENA |

REPOSITORIES: ENA

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DeltaNp63 silencing, DNA methylation shifts and epithelial mesenchymal transition resulted from TAp63 genome editing in squamous cell carcinoma [RRBS]

Project description:TP63 (p63) is strongly expressed in lower-grade carcinomas of head-and-neck, skin, breast, urothelium, etc. to maintain the well-differentiated phenotype. TP63 has two transcription start sites at exon 1 and exon 3’ to produce TAp63 and DeltaNp63 isoforms, respectively. The major protein, DeltaNp63alpha, functions as a core factor to organize super enhancers of genes essential for epidermal/craniofacial differentiation and for self-activation of DeltaNp63. To examine whether very weakly expressed TAp63 has a specific role, we disrupted exon 1 by CRISPR-Cas9 homology directed repair (HDR) in a head and neck squamous cell carcinoma (SCC) line. Surprisingly, TAp63 knockout cells, with either ‘monoallelic HDR and a frameshift deletion on the other allele’ or ‘biallelic HDR’, caused DeltaNp63 silencing. Loss of keratinocyte-specific gene expression, replacement of KRT5 with VIM, and transcriptional suppression of cell-cell and cell-matrix adhesion components indicated core events of epithelial mesenchymal transition. Most of the positively and negatively impacted genes including DeltaNp63 displayed local CpG methylation changes. Furthermore, DeltaNp63 expression was partially rescued by transfection of TAp63alpha, followed by incubation with DNA methyltransferase inhibitor Zebularine. This study suggests that TAp63 is indispensable for DeltaNp63 expression by which keratinocyte-specific epigenome is maintained in SCC.

2023-09-29 | GSE234979 | GEO

DeltaNp63 silencing, DNA methylation shifts and epithelial mesenchymal transition resulted from TAp63 genome editing in squamous cell carcinoma [microarray]

Project description:TP63 (p63) is strongly expressed in lower-grade carcinomas of head-and-neck, skin, breast, urothelium, etc. to maintain the well-differentiated phenotype. TP63 has two transcription start sites at exon 1 and exon 3’ to produce TAp63 and DeltaNp63 isoforms, respectively. The major protein, DeltaNp63alpha, epigenetically activates genes essential for epidermal/craniofacial differentiation, including DeltaNp63 itself. To examine whether weakly expressed TAp63 has a specific role, we disrupted exon 1 by CRISPR-Cas9 homology directed repair in a head and neck squamous cell carcinoma (SCC) line. Surprisingly, TAp63 knockout cells, either by monoallelic GFP cassette insertion paired with a frameshift deletion allele or by biallelic GFP cassette insertion, caused DeltaNp63 silencing. Loss of keratinocyte-specific gene expression, switching of intermediate filaments from KRT(s) to VIM, and suppression of cell-cell and cell-matrix adhesion components indicated core events of epithelial mesenchymal transition. Most of the positively and negatively impacted genes including DeltaNp63 displayed local DNA methylation changes. Furthermore, DeltaNp63 expression was partially rescued by transfection of TAp63alpha followed by incubation with DNA methyltransferase inhibitor Zebularine. TAp63, as a minor part of TP63 gene, may possibly be involved in the auto-activation mechanism of DeltaNp63 by which keratinocyte-specific epigenome is maintained in SCC.

2023-09-29 | GSE234978 | GEO

DeltaNp63 silencing, DNA methylation shifts and epithelial mesenchymal transition resulted from TAp63 genome editing in squamous cell carcinoma

Project description:DeltaNp63 silencing, DNA methylation shifts and epithelial mesenchymal transition resulted from TAp63 genome editing in squamous cell carcinoma

| PRJNA983828 | ENA

DeltaNp63 silencing, DNA methylation shifts and epithelial mesenchymal transition resulted from TAp63 genome editing in squamous cell carcinoma [RRBS]

Project description:DeltaNp63 silencing, DNA methylation shifts and epithelial mesenchymal transition resulted from TAp63 genome editing in squamous cell carcinoma [RRBS]

| PRJNA983834 | ENA

DeltaNp63 silencing, DNA methylation shifts and epithelial mesenchymal transition resulted from TAp63 genome editing in squamous cell carcinoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-09-29 | GSE234980 | GEO

TAp63 in pancreas cancer predicts the squamous subtype and promotes a suppressive immune micromilleu

Project description:To evaluate the role of aberrant TAp63 in PDAC, we analyzed transcriptomics by RNAseq in the TAp63 and deltaNP63 over-expressing pancreatic cancer cells.

2022-11-22 | GSE218268 | GEO

ΔNp63 silencing, DNA methylation shifts, and epithelial-mesenchymal transition resulted from TAp63 genome editing in squamous cell carcinoma.

Project description:TP63 (p63) is strongly expressed in lower-grade carcinomas of the head and neck, skin, breast, and urothelium to maintain a well-differentiated phenotype. TP63 has two transcription start sites at exons 1 and 3' that produce TAp63 and ΔNp63 isoforms, respectively. The major protein, ΔNp63α, epigenetically activates genes essential for epidermal/craniofacial differentiation, including ΔNp63 itself. To examine the specific role of weakly expressed TAp63, we disrupted exon 1 using CRISPR-Cas9 homology-directed repair in a head and neck squamous cell carcinoma (SCC) line. Surprisingly, TAp63 knockout cells having either monoallelic GFP cassette insertion paired with a frameshift deletion allele or biallelic GFP cassette insertion exhibited ΔNp63 silencing. Loss of keratinocyte-specific gene expression, switching of intermediate filament genes from KRT(s) to VIM, and suppression of cell-cell and cell-matrix adhesion components indicated the core events of epithelial-mesenchymal transition. Many of the positively and negatively affected genes, including ΔNp63, displayed local DNA methylation changes. Furthermore, ΔNp63 expression was partially rescued by transfection of the TAp63 knockout cells with TAp63α and application of DNA methyltransferase inhibitor zebularine. These results suggest that TAp63, a minor part of the TP63 gene, may be involved in the auto-activation mechanism of ΔNp63 by which the keratinocyte-specific epigenome is maintained in SCC.

| S-EPMC10544079 | biostudies-literature

Analysis of human TAp63 regulated genes in CD4+ T cells

Project description:By comparing the comprehensive gene expression profiles between human Th17 cells overexpressing TAp63 and those with TAp63 knockdown, FOXP3 was identified as one of the downregulated genes by TAp63

2023-04-10 | GSE181427 | GEO

FANCD2 Activates Transcription of TAp63 and Suppresses Tumorigenesis

Project description:Fanconi Anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population. Examination of FANCD2 binding after UV treatment in 293T cells

2013-06-27 | E-GEOD-46902 | biostudies-arrayexpress

TAp63-regulated microRNAs suppress cutaneous squamous cell carcinoma

Project description:TAp63 is a transcription factor belonging to the p53 family with important tumor suppressive functions. We show that TAp63-/- mice exhibit an increased susceptibility to UVR-induced cutaneous squamous cell carcinoma (cuSCC). These tumors showed global disruption of miRNA and mRNA expression when compared to tumors arising in wild-type mice. A comparison to similarly sequenced human cuSCC tumors identified miR-30c-2* and miR-497 as being significantly underexpressed in cuSCC. Reintroduction of these miRNAs significantly inhibited the growth of cuSCC cell lines and xenografts. Proteomic profiling of cells transfected with either miRNA showed significant downregulation of proteins related to cell cycle progression and mitosis. A cross-platform comparison of the RNAseq and proteomics signatures identified 7 downregulated proteins, which are also frequently overexpressed in both mouse and human cuSCC. Knockdown of AURKA, KIF18B, PKMYT1, and ORC1 in cuSCC cell lines suppressed tumor cell proliferation and induced cell death. Additionally, we found that an investigational, oral, selective inhibitor of AURKA suppressed cuSCC cell growth and induced cell death, and showed anti-tumor effects in vivo. Our data establishes TAp63 as an essential regulator of miRNA expression during skin carcinogenesis and reveals a novel network of miRNAs and mRNAs, which include potential targets for therapeutic intervention.

2020-07-07 | PXD014261 | Pride

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