Nuclear localization of TEF3-1 promotes cell cycle progression and angiogenesis in cancer

Teng, Kaixuan; Deng, Cuilan; Xu, Jie; Men, Qiuxu; Lei, Tao; Di, Da; Liu, Ting; Li, Wenhua; Liu, Xin

doi:10.18632/oncotarget.7342

Cited by 3 publications

(3 citation statements)

References 44 publications

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“…We have also revealed that E6-mediated upregulation of A3B is primarily caused by increased levels of TEAD1/4. A3B and TEAD1/4 are reported to be upregulated in various types of human cancer, and each has been proposed to play important roles in carcinogenesis (5)(6)(7)(8)(9)(28)(29)(30)(31)(32). This study thus establishes a novel transcriptional link between these oncogenic factors.…”

Section: Discussionmentioning

confidence: 55%

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

Mori

Takeuchi

Ishii

et al. 2017

J Virol

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The cytidine deaminase APOBEC3B (A3B) underlies the genetic heterogeneity of several human cancers, including cervical cancer, which is caused by human papillomavirus (HPV) infection. We previously identified a region within the A3B promoter that is activated by the viral protein HPV16 E6 in human keratinocytes. Here, we discovered three sites recognized by the TEAD family of transcription factors within this region of the A3B promoter. Reporter assays in HEK293 cells showed that exogenously expressed TEAD4 induced A3B promoter activation through binding to these sites. Normal immortalized human keratinocytes expressing E6 (NIKS-E6) displayed increased levels of TEAD1/4 protein compared to parental NIKS. A series of E6 mutants revealed that E6-mediated degradation of p53 was important for increasing TEAD4 levels. Knockdown of TEADs in NIKS-E6 significantly reduced A3B mRNA levels, whereas ectopic expression of TEAD4 in NIKS increased A3B mRNA levels. Finally, chromatin immunoprecipitation assays demonstrated increased levels of TEAD4 binding to the A3B promoter in NIKS-E6 compared to NIKS. Collectively, these results indicate that E6 induces upregulation of A3B through increased levels of TEADs, highlighting the importance of the TEAD-A3B axis in carcinogenesis.IMPORTANCE The expression of APOBEC3B (A3B), a cellular DNA cytidine deaminase, is upregulated in various human cancers and leaves characteristic, signature mutations in cancer genomes, suggesting that it plays a prominent role in carcinogenesis. Viral oncoproteins encoded by human papillomavirus (HPV) and polyomavirus have been reported to induce A3B expression, implying the involvement of A3B upregulation in virus-associated carcinogenesis. However, the molecular mechanisms causing A3B upregulation remain unclear. Here, we demonstrate that exogenous expression of the cellular transcription factor TEAD activates the A3B promoter. Further, the HPV oncoprotein E6 increases the levels of endogenous TEAD1/4 protein, thereby leading to A3B upregulation. Since increased levels of TEAD4 are frequently observed in many cancers, an understanding of the direct link between TEAD and A3B upregulation is of broad oncological interest.

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Section: Discussionmentioning

confidence: 55%

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

Mori

Takeuchi

Ishii

et al. 2017

J Virol

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“…TEAD3, also known as TEF-5, is a member of the transcriptional enhancer factor family of transcription factors that promotes the transcription of a number of cell proliferation-associated genes (such as cyclins and cyclin-dependent kinases) and leads to cell cycle progression, contributing to the development of cancer and drug resistance (40,41). It is, thus, speculated that its upstream miRNAs may be tumor suppressor genes.…”

Section: Discussionmentioning

confidence: 99%

Identification of exosomal and non‑exosomal microRNAs associated with the drug resistance of ovarian cancer

et al. 2019

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MicroRNAs (miRNAs) serve important roles in drug-resistance; however, exosomal miRNAs associated with drug-resistance in ovarian cancer (OC) have not been reported to date. The current study aimed to analyze the drug resistance-associated exosomal miRNAs in original OC cells and their derived exosomes using microarray data downloaded from the Gene Expression Omnibus database (series GSE76449). The chemosensitive OC cell lines SKOV3_ip1, A2780_PAR and HEYA8, as well as the chemoresistant cell lines SKOV3_TR, A2780_CP20 and HEYA8_MDR, were investigated. Differentially expressed miRNAs (DE-miRNAs) were identified using the limma method, and their mRNA targets were predicted using the miRWalk and LinkedOmics database. Functions of target genes were analyzed with DAVID tool, while TCGA data were used to explore the survival association of identified miRNAs. According to the results, 28 DE-miRNAs were found to be common in exosomal and original samples of A2780_CP20 cells, among which the functions of 5 miRNAs were predicted (including miR-146b-5p, miR-509-5p, miR-574-3p, miR-574-5p and miR-760). In addition, 16 and 35 DE-miRNAs were detected for HEYA8_MDR and SKOV3_TR, respectively, with the functions of 4 of these miRNAs predicted for each cell line (HEYA8_MDR: miR-30a-3p, miR-30a-5p, miR-612 and miR-617; SKOV3_TR: miR-193a-5p, miR-423-3p, miR-769-5p and miR-922). It was also reported that miR-183-5p was the only one common miRNA among the three cell lines. Furthermore, miR-574-3p, miR-30a-5p and miR-922 may regulate CUL2 to mediate HIF-1 cancer signaling pathway, while miR-183-5p may modulate MECP2, similar to miR-760, miR-30a-5p and miR-922, to influence cell proliferation. Finally, the downregulated miR-612 may promote the expression of TEAD3 via the Hippo signaling pathway, and this miRNA was associated with poor prognosis. In conclusion, the findings of the present study suggested several underlying miRNA targets for improving the chemotherapy sensitivity of OC.

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“…In gastric cancer, TEAD4 promotes cell cycle G1/S progression by increasing the expression of cyclins (D1 and E1) and CDKs (CDK2, 4, 6) ( Teng et al, 2016 ). It also augments the transcription of a lncRNA MNX1-AS1 which sequesters BCL2-targeting miR-6785-50, leading to up-regulation of pro-survival BCL2 (B-cell lymphoma 2) protein ( Shuai et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

TEAD4 as an Oncogene and a Mitochondrial Modulator

Hsu

Lin

et al. 2022

Front. Cell Dev. Biol.

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TEAD4 (TEA Domain Transcription Factor 4) is well recognized as the DNA-anchor protein of YAP transcription complex, which is modulated by Hippo, a highly conserved pathway in Metazoa that controls organ size through regulating cell proliferation and apoptosis. To acquire full transcriptional activity, TEAD4 requires co-activator, YAP (Yes-associated protein) or its homolog TAZ (transcriptional coactivator with PDZ-binding motif) the signaling hub that relays the extracellular stimuli to the transcription of target genes. Growing evidence suggests that TEAD4 also exerts its function in a YAP-independent manner through other signal pathways. Although TEAD4 plays an essential role in determining that differentiation fate of the blastocyst, it also promotes tumorigenesis by enhancing metastasis, cancer stemness, and drug resistance. Upregulation of TEAD4 has been reported in several cancers, including colon cancer, gastric cancer, breast cancer, and prostate cancer and serves as a valuable prognostic marker. Recent studies show that TEAD4, but not other members of the TEAD family, engages in regulating mitochondrial dynamics and cell metabolism by modulating the expression of mitochondrial- and nuclear-encoded electron transport chain genes. TEAD4’s functions including oncogenic activities are tightly controlled by its subcellular localization. As a predominantly nuclear protein, its cytoplasmic translocation is triggered by several signals, such as osmotic stress, cell confluency, and arginine availability. Intriguingly, TEAD4 is also localized in mitochondria, although the translocation mechanism remains unclear. In this report, we describe the current understanding of TEAD4 as an oncogene, epigenetic regulator and mitochondrial modulator. The contributing mechanisms will be discussed.

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Nuclear localization of TEF3-1 promotes cell cycle progression and angiogenesis in cancer

Cited by 3 publications

References 44 publications

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

Identification of exosomal and non‑exosomal microRNAs associated with the drug resistance of ovarian cancer

TEAD4 as an Oncogene and a Mitochondrial Modulator

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