A splicing isoform of TEAD4 attenuates the Hippo–YAP signalling to inhibit tumour proliferation

Qi, Yangfan; Yu, Jing; Han, Wei; Fan, Xiaojuan; Qian, Haili; Wei, Huanhuan; Tsai, Yi-Hsuan; Zhao, Jie; Zhang, Wenjing; Liu, Quentin; Shao, Meng; Wang, Yan; Wang, Zefeng

doi:10.1038/ncomms11840

Cited by 64 publications

(69 citation statements)

References 54 publications

(58 reference statements)

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“…The splicing factor RBM4 suppresses proliferation and migration in various cancers by specifically controlling cancer-related splicing 5–9. Wang et al4 reported that RBM4 regulates Bcl-x splicing to induce apoptosis and RBM4 expression is decreased dramatically in human cancer such as lung, breast and ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

Decrease of RBM4 indicates poor prognosis in patients with hepatocellular carcinoma after hepatectomy

Chen¹,

Liu²,

Xu³

2017

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RNA-binding motif 4 (RBM4) has been reported to play an important role in many human tumors such as lung cancer, breast cancer, ovarian cancer and gastric cancer by regulating alternative splicing and messenger RNA (mRNA) translation. However, little is known about the role of RBM4 in the development of hepatocellular carcinoma (HCC). This study aimed to investigate the expression of RBM4 in HCC tissues. Expression of RBM4 was detected by immunohistochemistry in 95 cases of HCC. Correlations of RBM4 expression with the overall survival and disease-free survival of HCC were also studied. Patients with high RBM4 expression had better overall survival rate and disease-free survival rate than those with low RBM4 expression (P<0.001, P=0.007, respectively). RBM4 expression, together with tumor numbers, capsular formation, vascular invasion and Barcelona clinic liver cancer (BCLC) stage, was an independent prognostic factor for overall survival rate and disease-free survival rate of HCC. Our data implicate RBM4 as a novel prognostic marker and a potential therapeutic target for HCC.

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Section: Discussionmentioning

confidence: 99%

Decrease of RBM4 indicates poor prognosis in patients with hepatocellular carcinoma after hepatectomy

Chen¹,

Liu²,

Xu³

2017

OTT

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“…By inhibiting the YAP signaling, the short isoform is responsible for the dysregulation of cell cycle, cell proliferation and RNA processing pathways normally activated by YAP-TEAD4-FL interaction [113,114]. The two isoforms show the opposite roles in cancer in vitro and in vivo, with TEAD4-FL being a tumor promoter and TEAD4-S a tumor suppressor [115]. Clinical investigation and TCGA data analysis highlighted that TEAD4-S expression is commonly reduced in human cancers and patients with elevated TEAD4-S levels show improved survival [111,115].…”

Section: Tea Domain Family Member 4 (Tead4)mentioning

confidence: 99%

“…The two isoforms show the opposite roles in cancer in vitro and in vivo, with TEAD4-FL being a tumor promoter and TEAD4-S a tumor suppressor [115]. Clinical investigation and TCGA data analysis highlighted that TEAD4-S expression is commonly reduced in human cancers and patients with elevated TEAD4-S levels show improved survival [111,115]. In particular, in lung cancer cells, which have lower TEAD4-S level compared with normal cells, TEAD4-FL activates transcription of N-cadherin and vimentin genes inducing EMT of tumor cells, while TEAD4-S suppresses EMT markers [115].…”

Section: Tea Domain Family Member 4 (Tead4)mentioning

confidence: 99%

“…Clinical investigation and TCGA data analysis highlighted that TEAD4-S expression is commonly reduced in human cancers and patients with elevated TEAD4-S levels show improved survival [111,115]. In particular, in lung cancer cells, which have lower TEAD4-S level compared with normal cells, TEAD4-FL activates transcription of N-cadherin and vimentin genes inducing EMT of tumor cells, while TEAD4-S suppresses EMT markers [115]. RBM4, a splicing factor that functions as a tumor suppressor in many cancers, has been pointed out as a possible regulator of TEAD4 splicing of exon 3.…”

Section: Tea Domain Family Member 4 (Tead4)mentioning

confidence: 99%

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Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates

Belluti

Rigillo

Imbriano

2020

Cells

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Alternative splicing (AS) is a finely regulated mechanism for transcriptome and proteome diversification in eukaryotic cells. Correct balance between AS isoforms takes part in molecular mechanisms that properly define spatiotemporal and tissue specific transcriptional programs in physiological conditions. However, several diseases are associated to or even caused by AS alterations. In particular, multiple AS changes occur in cancer cells and sustain the oncogenic transcriptional program. Transcription factors (TFs) represent a key class of proteins that control gene expression by direct binding to DNA regulatory elements. AS events can generate cancer-associated TF isoforms with altered activity, leading to sustained proliferative signaling, differentiation block and apoptosis resistance, all well-known hallmarks of cancer. In this review, we focus on how AS can produce TFs isoforms with opposite transcriptional activities or antagonistic functions that severely impact on cancer biology. This summary points the attention to the relevance of the analysis of TFs splice variants in cancer, which can allow patients stratification despite the presence of interindividual genetic heterogeneity. Recurrent TFs variants that give advantage to specific cancer types not only open the opportunity to use AS transcripts as clinical biomarkers but also guide the development of new anti-cancer strategies in personalized medicine.

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“…Therefore, a PUF scaffold can be modified to recognize any 8-nt RNA sequence with a reprogrammable RNA binding code (Cheong and Hall, 2006;Dong et al, 2011;Filipovska et al, 2011). By combining a customized PUF domain with splicing regulatory domains, we were able to specifically promote or suppress AS of various targets (Qi et al, 2016;Wang et al, 2009;Wang et al, 2012;Wang et al, 2013).…”

Section: Design and Validation Of Esfs That Regulate Alternative Splimentioning

confidence: 99%

Modeling and Predicting the Activities of Trans-Acting Splicing Factors with Machine Learning

Mao

Yang

et al. 2018

Cell Systems

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Graphical Abstract Highlights d Most low-complexity domains in RBPs can regulate splicing when recruited to pre-mRNAs d Splicing regulatory activities of RBPs are mainly determined by sequence composition d Machine learning approach was developed to predict splicing regulatory activity of RBPs d The predictive model facilitates the design of artificial factors to manipulate splicing Correspondence wangzefeng@picb.an.cn In BriefAlternative splicing is mainly regulated by various trans-acting splicing factors that specifically bind cis-elements. A systematic survey was conducted to study splicing regulatory activities of many RBPs, providing a training set for a machine learning approach to predict splicing regulatory activities of endogenous RBPs and synthetic peptides. This study expanded the repertoire of potential splicing factors and revealed a direct link between the sequence composition and RBP activity. SUMMARYAlternative splicing (AS) is generally regulated by trans-splicing factors that specifically bind to cis-elements in pre-mRNAs. The human genome encodes $1,500 RNA binding proteins (RBPs) that potentially regulate AS, yet their functions remain largely unknown. To explore their potential activities, we fused the putative functional domains of RBPs to a sequence-specific RNA-binding domain and systemically analyzed how these engineered factors affect splicing. We discovered that $80% of lowcomplexity domains in endogenous RBPs displayed distinct context-dependent activities in regulating splicing, indicating that AS is under more extensive regulation than previously expected. We developed a machine learning approach to classify and predict the activities of RBPs based on their sequence compositions and further validated this model using endogenous RBPs and synthetic polypeptides. These results represent a systematic inspection, modeling, prediction, and validation of how RBP sequences affect their activities in controlling splicing, paving the way for de novo engineering of artificial splicing factors.

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A splicing isoform of TEAD4 attenuates the Hippo–YAP signalling to inhibit tumour proliferation

Cited by 64 publications

References 54 publications

Decrease of RBM4 indicates poor prognosis in patients with hepatocellular carcinoma after hepatectomy

Decrease of RBM4 indicates poor prognosis in patients with hepatocellular carcinoma after hepatectomy

Transcription Factors in Cancer: When Alternative Splicing Determines Opposite Cell Fates

Modeling and Predicting the Activities of Trans-Acting Splicing Factors with Machine Learning

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