Analysis of the differential expression of genes in Otub2- knockout mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE171878 | GEO | 2022/09/19
REPOSITORIES: GEO
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Project description:Oral and esophageal squamous cell carcinomas (SCCs) are associated with high mortality, yet molecular mechanisms underlying these malignancies are largely unknown. We demonstrate that epigenetic silencing of otubain 2 (OTUB2), a previously recognized oncogene, drives SSCs initiation and drug resistance. Mechanistically, OTUB2 promotes deubiquitination and phosphorylation of signal transducer and activator of transcription 1 (STAT1), then activates transcriptional regulation of calmodulin-like protein 3 (CALML3). Activation of CALML3-mediated mitochondrial calcium signaling promotes oxidative phosphorylation (OXPHOS) and glycerophospholipid synthesis, among which phosphatidylserine (PS) is the most obviously affected. Orally administered soybean-derived PS dramatically inhibits low-OTUB2-expressed SCC initiation and increased sensitivity to chemotherapy in various mouse models. Our study indicates that the OTUB2/STAT1/CALML3/PS axis plays a critical tumor-suppressive role in SCCs, clarifies the low incidence of oral and esophageal SCCs in Western countries with a high-fat diet and demonstrates the potential of food supplementation with PS as a strategy for treatment and prevention of SCCs.
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Project description:SOX2 is a transcription factor essential for pluripotent stem cells, and development and maintenance of squamous epithelium. We previously reported SOX2 an oncogene subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here we demonstrate in SCCs that SOX2 interacts with another master squamous transcription factor p63, and through ChIP-seq show that genomic occupancy of SOX2 overlaps with that of p63 at a large number of loci and that they cooperatively regulate gene expression including ETV4, which we find essential for SOX2-amplified SCC cell survival. Furthermore, SOX2 binds to distinct genomic loci in SCCs than in embryonic stem cells and the SOX2-p63 coordinate binding is unique to SCC. In addition, a subset of SOX2 genomic binding sites in SCC that lack p63 co-occupancy are co-occupied by the AP-1 transcriptional complex. These demonstrate that SOX2’s actions in SCC differ substantially from its role in pluripotency and identify novel SOX2 interactions that will enable deeper characterization of SOX2’s function in SCC. SOX2 and p63 ChIP-seq from three lung and esophageal squamous carcinoma cell lines with amplification of SOX2 as well as SOX2 ChIP-seq from an ES cells.
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Project description:Lineage-survival oncogenes are targeted by gene amplification in cancers arising from the tissues where these genes play a role in normal development. Here we show that the transcription factor SOX2—previously known to be mutated in hereditary human esophageal malformations, to be necessary for normal esophageal squamous development, to promote proliferation of basal tracheal cells and to co-operate in induction of pluripotent stem cells -- acts as an amplified oncogene in squamous cell carcinomas (SCC) of the lung and esophagus. We identified SOX2 at a peak of genomic amplification on chromosome 3q26.33 in SCCs of both the lung and esophagus but did not find it to be significantly amplified in adenocarcinomas from these tissues. Tumors with SOX2 amplification showed higher SOX2 mRNA expression, and suppression of SOX2 by RNAi in lung and esophageal SCC cell lines revealed that SOX2 expression is required for proliferation and anchorage-independent growth. Furthermore, ectopic expression of SOX2 cooperated with FOXE1 or FGFR2 to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors showed expression of markers of both squamous differentiation and pluripotency. These observations identify SOX2 as a novel lineage survival oncogene in lung and esophageal SCC and suggest novel connections between development, pluripotency and carcinogenesis.
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Project description:SOX2 is a transcription factor essential for pluripotent stem cells, and development and maintenance of squamous epithelium. We previously reported SOX2 an oncogene subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here we demonstrate in SCCs that SOX2 interacts with another master squamous transcription factor p63, and through ChIP-seq show that genomic occupancy of SOX2 overlaps with that of p63 at a large number of loci and that they cooperatively regulate gene expression including ETV4, which we find essential for SOX2-amplified SCC cell survival. Furthermore, SOX2 binds to distinct genomic loci in SCCs than in embryonic stem cells and the SOX2-p63 coordinate binding is unique to SCC. In addition, a subset of SOX2 genomic binding sites in SCC that lack p63 co-occupancy are co-occupied by the AP-1 transcriptional complex. These demonstrate that SOX2’s actions in SCC differ substantially from its role in pluripotency and identify novel SOX2 interactions that will enable deeper characterization of SOX2’s function in SCC.
2014-03-12 | GSE46837 | GEO
Project description:SOX2 is a transcription factor essential for pluripotent stem cells, and development and maintenance of squamous epithelium. We previously reported SOX2 an oncogene subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs)1. Here we demonstrate in SCCs that SOX2 interacts with another master squamous transcription factor p63, and through ChIP-seq show that genomic occupancy of SOX2 overlaps with that of p63 at a large number of loci and that they cooperatively regulate gene expression including ETV4, which we find essential for SOX2-amplified SCC cell survival. Furthermore, SOX2 binds to distinct genomic loci in SCCs than in embryonic stem cells and the SOX2-p63 coordinate binding is unique to SCC. In addition, a subset of SOX2 genomic binding sites in SCC that lack p63 co-occupancy are co-occupied by the AP-1 transcriptional complex. These demonstrate that SOX2’s actions in SCC differ substantially from its role in pluripotency and identify novel SOX2 interactions that will enable deeper characterization of SOX2’s function in SCC.
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Project description:RNA-Seq was applied to oral squamous cell carcinomas and matched normal oral tissue to measure gene expression patterns and identify examples of allelic imbalance. Oral squamous cell carcinomas (OSCC) and matched normal tissue from 3 patients.
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Project description:Clinically evident oral lesions, oral epithelial dysplasia, precede development of oral squamous cell carcinomas (SCC) and are considered to transform to cancer by acquisition of genetic or epigenetic alterations. Here, we show that, +3q24-qter, -8pter-p23.1, +8q12-q24.2 and +20 are early events identifying two pathways to oral cancers that differ in clinical behavior. One or more of these copy number aberrations is present in the major subgroup (3q8pq20 subtype, 75-80% of lesions) that develops with chromosomal instability and risk for metastasis, while they are absent from the smaller and chromosomally stable non-3q8pq20 subgroup (20-25% of lesions) associated with low risk for metastasis. Thus, +3q, -8p, +8q and +20 is a biomarker for oral SCC metastasis. On the other hand, while increased numbers of genomic alterations can be harbingers of progression to cancer, dysplastic lesions lacking copy number changes cannot be considered benign as they are potential precursors to non-3q8pq20 oral SCC. 63 oral SCCs and adjacent regions of normal tissue, 44 oral dysplasias
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