Increased TEAD4 expression and nuclear localization in colorectal cancer promote epithelial–mesenchymal transition and metastasis in a YAP-independent manner

Y, Liu; Wang, G; Yang, Yong; Zhong, Mei; Liang, Zhonglin; A, Cui; Wu, Tong; Cy, Liu; L, Cui

doi:10.1038/onc.2015.342

Cited by 116 publications

(133 citation statements)

References 38 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: 72%

“…Of particular interest, TEAD4 is overexpressed in several human cancers, such as gastric, breast, and colorectal cancers, and the expression levels of TEAD4 correlate with poor survival of cancer patients (20,(29)(30)(31). Whether such TEAD4 upregulation leads to A3B upregulation in these cancers, thereby contributing to cancer evolution and malignancies, warrants further investigation using cell culture models and clinical specimens.…”

Section: Figmentioning

confidence: 99%

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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: 72%

Section: Figmentioning

confidence: 99%

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

Mori

Takeuchi

Ishii

et al. 2017

J Virol

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“…While prior studies have indicated TEAD4 driving previously identified YAP/TEAD targets in neuroblastoma cells (62, 80), these studies were performed in MYCN WT cells, further confirming that different regulatory mechanisms are at play in MYCN Amp versus MYCN WT cells. Interestingly, studies in mammary tumors have shown that MYC represses YAP/TAZ activity, while also showing that MYC induction decreases binding of YAP/TAZ to its bona fide targets, CTGF and CYR61, but not of TEAD4 (81); additional studies have shown YAP/TAZ-independent regulatory activity of TEAD4 (82). In contrast to the canonical view that TEAD4 lacks independent transcriptional activation (83), TEAD4 was also recently reported to have a transcriptional activation domain, supporting transcriptional regulation independent of the YAP/TAZ DNA binding domain (84).…”

Section: Discussionmentioning

confidence: 99%

Cross-Cohort Analysis Identifies a TEAD4–MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma

et al. 2018

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High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator (MR) proteins that were conserved across independent cohorts. A 10–protein transcriptional module – centered around a TEAD4 ↔ MYCN positive-feedback loop – emerged as the regulatory driver of the high-risk subtype associated with MYCN amplification. Silencing of either gene collapsed MYCN-amplified (MYCNAmp) neuroblastoma transcriptional hallmarks and abrogated viability in vitro and in vivo. Consistently, TEAD4 emerged as a robust prognostic marker of poor survival, with activity independent of the canonical Hippo pathway transcriptional co-activators, YAP and TAZ. These results suggest novel therapeutic strategies for the large subset of MYCN deregulated neuroblastomas.

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“…These studies have emphasized the role of YAP/TAZ amplification and hyperactivity in various cancers [66], however increased TEAD expression and activity, both dependent and independent of YAP/TAZ, have also been implicated in the progression of several solid tumors [7] (Table 1). High TEAD expression levels are seen in prostate, colorectal, and breast cancers and, concordantly, are an indicator of poor clinical outcome [67–71]. In breast cancer cells, induction of epithelial to mesenchymal transition (EMT) resulted in upregulation of TEAD2 and a marked increase in YAP/TAZ nuclear accumulation despite decreases in overall YAP/TAZ protein levels [70].…”

Section: Tead Regulation In Cancersmentioning

confidence: 99%

Regulation of the Hippo Pathway Transcription Factor TEAD

Lin

Park

Guan

2017

Trends in Biochemical Sciences

258

206

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The TEAD transcription factor family is best known for transcriptional output of the Hippo signaling pathway and has been implicated in processes such as development, cell growth and proliferation, tissue homeostasis, and regeneration. Our understanding of the functional importance of TEADs has increased dramatically since its initial discovery three decades ago. The majority of our knowledge of TEADs is in the context of Hippo signaling as nuclear DNA binding proteins passively activated by YAP and TAZ, transcription coactivators downstream of the Hippo pathway. However, recent studies suggest that TEAD itself is actively regulated. Here, we highlight evidence demonstrating Hippo-independent regulation of TEADs and the potential impacts these studies may have on new cancer therapeutics.

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Increased TEAD4 expression and nuclear localization in colorectal cancer promote epithelial–mesenchymal transition and metastasis in a YAP-independent manner

Cited by 116 publications

References 38 publications

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

Cross-Cohort Analysis Identifies a TEAD4–MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma

Regulation of the Hippo Pathway Transcription Factor TEAD

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