Role of T‐box genes in cancer, epithelial‐mesenchymal transition, and cancer stem cells

Niu, Gengle; Hao, Jin; Sui, Sheng; Wen, Fangyuan

doi:10.1002/jcb.30188

Cited by 8 publications

(6 citation statements)

References 141 publications

(150 reference statements)

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“…All 17 members of the T-box family of genes are expressed postnatally in highly cell- or tissue-specific patterns ( Table S1 ) consistent with their important roles in development [ 3 , 25 ]. Like TBX15 and TBX18 , three other T-box genes, TBX2 , TBX3 , and TBX1 , were more highly expressed in myoblasts than most or all the five other diverse cell culture types in an ENCODE database ( Table S3 ).…”

Section: Resultsmentioning

confidence: 94%

Promoter-Adjacent DNA Hypermethylation Can Downmodulate Gene Expression: TBX15 in the Muscle Lineage

et al. 2022

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TBX15, which encodes a differentiation-related transcription factor, displays promoter-adjacent DNA hypermethylation in myoblasts and skeletal muscle (psoas) that is absent from non-expressing cells in other lineages. By whole-genome bisulfite sequencing (WGBS) and enzymatic methyl-seq (EM-seq), these hypermethylated regions were found to border both sides of a constitutively unmethylated promoter. To understand the functionality of this DNA hypermethylation, we cloned the differentially methylated sequences (DMRs) in CpG-free reporter vectors and tested them for promoter or enhancer activity upon transient transfection. These cloned regions exhibited strong promoter activity and, when placed upstream of a weak promoter, strong enhancer activity specifically in myoblast host cells. In vitro CpG methylation targeted to the DMR sequences in the plasmids resulted in 86–100% loss of promoter or enhancer activity, depending on the insert sequence. These results as well as chromatin epigenetic and transcription profiles for this gene in various cell types support the hypothesis that DNA hypermethylation immediately upstream and downstream of the unmethylated promoter region suppresses enhancer/extended promoter activity, thereby downmodulating, but not silencing, expression in myoblasts and certain kinds of skeletal muscle. This promoter-border hypermethylation was not found in cell types with a silent TBX15 gene, and these cells, instead, exhibit repressive chromatin in and around the promoter. TBX18, TBX2, TBX3 and TBX1 display TBX15-like hypermethylated DMRs at their promoter borders and preferential expression in myoblasts. Therefore, promoter-adjacent DNA hypermethylation for downmodulating transcription to prevent overexpression may be used more frequently for transcription regulation than currently appreciated.

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Section: Resultsmentioning

confidence: 94%

Promoter-Adjacent DNA Hypermethylation Can Downmodulate Gene Expression: TBX15 in the Muscle Lineage

et al. 2022

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“…For example, we discovered that TBX15 was the most highly upregulated gene in the advanced maternal age group, while RBP4 was the most downregulated. TBX15 is a gene expressed by epithelial cancer cells and associated with epithelial to mesenchymal transition (EMT) 12 . The upregulation of TBX15 reduces apoptosis through NF-κB 13 .…”

Section: Discussionmentioning

confidence: 99%

Aging affects ciliated cells development in the human endometrial epithelium

Loid

Obukhova

Kask

et al. 2023

Preprint

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The twenties are typically considered the prime reproductive years for women. However, in today’s modern world, many women are choosing to delay family planning, resulting in an increase of females in their forties seeking fertility treatment. Althoughin vitrofertilization (IVF) with donated oocytes and preimplantation genetic testing may help to address the impact of maternal age, the success rate for IVF treatment in this age group is still significantly lower. While endometrial changes, such as abnormal endometrial thickness, inflammatory background, and altered hormone response signaling, are associated with aging, little is known about the molecular features of endometrial aging and their impact on the ability to support embryo implantation. To better understand age-specific changes, we performed endometrial transcriptome profiling of young and advanced age females, undergoing hormonal replacement therapy (HRT) before frozen embryo transfer, followed by immunohistology analysis and single-cell-based deconvolution. Here, we identified 491 differentially expressed genes pointing to the effect of aging on decidualization, cell signaling, inflammation and endometrial receptivity. Our results indicate that p16INK4amay be involved in cellular senescence and the suppression of metabolic and inflammatory processes essential for endometrial preparation for embryo implantation. We have also shown that the proportion of ciliated cells along with ciliary processes is affected by endometrial aging. These findings have important implications for future strategies aimed at improving infertility treatment in women of advanced reproductive age.

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“…Lipid metabolism was significantly and positively correlated with epithelial mesenchymal transition (EMT), PI3K/Akt/mTOR signaling, mTOR complex 1 (mTORC1) signaling, MYC targets V1, reactive oxygen species (ROS) pathway and xenobiotic metabolism. EMT is an important initiating process in the metastasis of tumor cells, allowing epithelial cells to lose apical-basal polarity and cell–cell adhesion, and acquire mobility and invasiveness [ 28 , 29 ]. PI3K/AKT/mTOR pathway regulates a variety of cellular processes including growth, proliferation, metastasis and radiosensitivity [ 30 – 32 ].…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of transcription factor-driven enhancers of genes related to lipid metabolism in metastatic oral squamous cell carcinomas

et al. 2022

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Background The role and mechanisms of lipid metabolism in oral squamous cell carcinomas (OSCC) metastasis have not been clarified. This study aims to identify lipid metabolism-related genes and transcription factors regulated by metastasis-associated enhancers (MAEs) in OSCC. Methods Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were performed for lipid metabolism enrichment. TCGA data were used to analyze the differentially expressed lipid metabolism-related genes. MAEs were analyzed using GSE120634. Overlapping analysis was used to screen the MAE-regulated lipid metabolism-related genes, and the prognosis of these genes was analyzed. Transcription factor prediction was performed for the MAE-regulated lipid metabolism-related genes with prognostic value. Validation of the metastatic specificity of MAEs at ACAT1, OXSM and VAPA locus was performed using GSE88976 and GSE120634. ChIP-qPCR, qRT-PCR and Western blotting were used to verify the regulation of ACAT1, OXSM and VAPA expression by CBFB. Effects of CBFB knockdown on proliferation, invasion and lipid synthesis in metastatic OSCC cells were analyzed. Results Lipid metabolism was significantly enhanced in metastatic OSCC compared to non-metastatic OSCC. The expression of 276 lipid metabolism-related genes was significantly upregulated in metastatic OSCC, which were functionally related to lipid uptake, triacylglycerols, phospholipids and sterols metabolism. A total of 6782 MAEs and 176 MAE-regulated lipid metabolism-related genes were filtered. Three MAE-regulated lipid metabolism-related genes, ACAT1, OXSM and VAPA, were associated with a poor prognosis in OSCC patients. Enhancers at ACAT1, OXSM and VAPA locus were metastasis-specific enhancers. CBFB regulated ACAT1, OXSM and VAPA expression by binding to the enhancers of these genes. Knockdown of CBFB inhibited proliferation, invasion and lipid synthesis in metastatic OSCC cells. Conclusion The MAE-regulated lipid metabolism-related genes (ACAT1, OXSM and VAPA) and the key transcription factor (CBFB) were identified. CBFB knockdown inhibited proliferation, invasion and lipid synthesis of OSCC cells. These findings provide novel candidates for the development of therapeutic targets for OSCC.

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Role of T‐box genes in cancer, epithelial‐mesenchymal transition, and cancer stem cells

Cited by 8 publications

References 141 publications

Promoter-Adjacent DNA Hypermethylation Can Downmodulate Gene Expression: TBX15 in the Muscle Lineage

Promoter-Adjacent DNA Hypermethylation Can Downmodulate Gene Expression: TBX15 in the Muscle Lineage

Aging affects ciliated cells development in the human endometrial epithelium

Identification and validation of transcription factor-driven enhancers of genes related to lipid metabolism in metastatic oral squamous cell carcinomas

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