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A splicing switch of TEAD4 regulates Hippo-YAP signaling pathway to inhibit tumor proliferation

ABSTRACT: Splicing dysregulations extensively occur in cancers, yet the biological consequences of such alterations are mostly undefined. Here we report that the Hippo-YAP signaling, a key pathway that regulates cell proliferation and organ size, is under control of a new splicing switch. We show that TEAD4, the transcription factor that mediates Hippo-YAP signaling, undergoes alternative splicing facilitated by the tumor suppressor RBM4, producing a truncated isoform, TEAD4-S, which lacks N-terminal DNA-binding domain but maintains YAP-interaction domain. TEAD4-S is located in both nucleus and cytoplasm, acting as a dominant negative isoform to YAP activity. Consistently, TEAD4-S is reduced in cancer cells, and its re-expression suppresses cancer cell proliferation and migration, inhibiting tumor growth in xenograft mouse model. Furthermore, TEAD4-S is reduced in human cancers, and patients with elevated TEAD4-S levels have improved survival. Altogether these data reveal a novel RBM4-mediated splicing switch that serves to fine-tune Hippo-YAP pathway.

ORGANISM(S): Homo sapiens

PROVIDER: GSE80372 | GEO | 2016/06/16

SECONDARY ACCESSION(S): PRJNA318757

REPOSITORIES: GEO

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A splicing switch of TEAD4 regulates Hippo-YAP signaling pathway to inhibit tumor proliferation

Project description:Splicing dysregulations extensively occur in cancers, yet the biological consequences of such alterations are mostly undefined. Here we report that the Hippo-YAP signaling, a key pathway that regulates cell proliferation and organ size, is under control of a new splicing switch. We show that TEAD4, the transcription factor that mediates Hippo-YAP signaling, undergoes alternative splicing facilitated by the tumor suppressor RBM4, producing a truncated isoform, TEAD4-S, which lacks N-terminal DNA-binding domain but maintains YAP-interaction domain. TEAD4-S is located in both nucleus and cytoplasm, acting as a dominant negative isoform to YAP activity. Consistently, TEAD4-S is reduced in cancer cells, and its re-expression suppresses cancer cell proliferation and migration, inhibiting tumor growth in xenograft mouse model. Furthermore, TEAD4-S is reduced in human cancers, and patients with elevated TEAD4-S levels have improved survival. Altogether these data reveal a novel RBM4-mediated splicing switch that serves to fine-tune Hippo-YAP pathway. Cell lines stably expressing YAP, YAP/TEAD4-S, YAP/TEAD4-FL, YAP/RBM4 and control vector were created, and the total RNA was purified from the cells using TRIzol reagents. The polyadenylated RNAs were purified for construction of sequencing library using kapa TruSeq Total RNA Sample Prep kits (UNC High Throughput Sequencing Facility).

2016-06-16 | E-GEOD-80372 | biostudies-arrayexpress

The Role and Mechanism of TEAD4 in Preimplantation Embryonic Development in Mice and Cattle

Project description:Tead4 is a critical transcription factor expressed during preimplantation development and is essential for the expression of trophectoderm-specific genes in mice. However, the mechanism of Tead4’s function in mouse preimplantation development and its conservation across mammals remains unclear. Here, we report that Tead4 is a crucial transcription factor necessary for blastocyst formation in mice. Disruption of TEAD4 through base editing results in developmental arrest at the morula stage. Additionally, RNA-seq analysis reveals dysregulation of 670 genes in Tead4 knockout embryos. As anticipated, Tead4 knockout leads to a decrease in trophectoderm genes CDX2 and GATA3. Intriguingly, we observed a reduction in KRT8, suggesting that Tead4 influences the integrity of the trophectoderm epithelium in mice. More importantly, we noted a decrease in nuclear YAP for Tead4-deficient embryos, indicating that Tead4 directly regulates Hippo signaling. In contrast, bovine embryos with TEAD4 depletion can still develop to blastocysts with normal expression of CDX2, GATA3, and SOX2, albeit with a decrease in total cell number and ICM cell number. In conclusion, we propose that Tead4 regulates mouse blastocyst formation via Krt8 and Yap, both of which are critical regulators of mouse preimplantation development.

2024-07-15 | GSE237418 | GEO

Impact of Verteporfin on HCC cells

Project description:Together with TEAD4 the Hippo pathway effector YAP stimulates chromosomal instability. Verteporfin is known to disrupt the physical YAP/TEAD interaction and tehrefore might prevent from chromosomal instability in liver cancer. Immortalized HCC cell line hepG2 is treated with Verteporfin for 24 hours.

2016-02-11 | E-GEOD-73396 | biostudies-arrayexpress

Homo sapiens

Project description:A splicing switch of TEAD4 regulates Hippo-YAP signaling pathway to inhibit tumor proliferation

| PRJNA318757 | ENA

ROBO3s: a novel ROBO3 shot isoform promoting breast cancer aggressiveness

Project description:We identified a novel uncharacterized short isoform of the Roundabout Guidance Receptor 3 (ROBO3) encoding for the C-terminal domain of the protein and lacking transmembrane region. We established an important role for the so-called ROBO3s isoform, mediating cancer stem cell properties by stimulating the Hippo-YAP signaling pathway, and thus driving the resistance of Basal-like breast cancer cells to cytotoxic drugs.

2022-08-31 | E-MTAB-10744 | biostudies-arrayexpress

TEAD4 occupied genes in differentiated C2C12 myoblasts

Project description:The TEAD (1-4) transcription factors comprise the conserved TEA/ATTS DNA binding domain recognising the MCAT element in the promoters of muscle-specific genes. Despite extensive genetic analysis, the function of TEAD factors in muscle differentiation has proved elusive due to redundancy amongst the family members. Expression of the TEA/ATTS DNA binding domain that acts a dominant negative repressor of TEAD factors in C2C12 myoblasts inhibits their differentiation, while selective shRNA knockdown of TEAD4 results in abnormal differentiation characterised by the formation of shortened myotubes. Chromatin immunoprecipitation coupled to array hybridisation (ChIP-chip) shows that TEAD4 occupies 867 promoters including those of myogenic miRNAs. We show that TEAD factors cooperate with MYOD1 to directly induce Myogenin, CDKN1A and Caveolin 3 expression to promote myoblast differentiation and fusion. RNA-seq identifies a novel set of TEAD4 target genes encoding muscle structural and regulatory proteins and those required for the unfolded protein response. In contrast, TEAD4 represses expression of the growth factor CTGF and Cyclin D1 to promote differentiation. Together these results show that TEAD factor activity is essential for C2C12 cell differentiation and define a novel and nonredundant role for TEAD4 in regulating the unfolded protein response. C2C12 cells were infected with retrotiviral vector expressing Flag-HA-Tagged TEAD4 or with empty control vector and selected in the continouos presence of puromycin. Infected cell populations were then differentiated for 5 days in DMEM medium with 2% horse serum and fixed in 0.4% formaldehyde.

2011-08-21 | E-GEOD-29208 | biostudies-arrayexpress

TEAD4

Project description:TEAD4

| PRJNA604980 | ENA

YAP targets TEAD4-NF-κB complex and inhibits ccRCC tumor growth

Project description:The prevalent understanding of Hippo signaling is one inhibitory pathway in tumor growth via deactivating the potential of YAP-TEAD transcriptional complex. The aberrant activation of YAP was observed in a series of human malignancies. However, recent studies implicate that in certain cancer types, YAP could be a tumor suppressor. Here, we reported a context-dependent function of YAP in clear cell renal carcinoma (ccRCC). Inhibition of Hippo kinase activity impeded ccRCC tumor growth and NF-κB transcriptional programs. Pharmacological blocking Hippo kinase activity or ectopic activation of YAP suppressed tumor growth in xenograft and PDX models. Mechanism studies revealed that TEAD could synchronize with P65 for NF-κB signaling activation, while YAP disrupted TEAD-NF-κB interactions and dissociated P65 from its target gene promoter, thereby inhibiting NF-κB transcriptional programs and ccRCC tumor growth. Our study identified a novel crosstalk between Hippo and NF-κB pathway, uncovered a non-canonical regulation of Hippo/YAP axis in renal cancer and suggested a novel strategy to ccRCC treatments by YAP activation.

2024-05-31 | GSE252142 | GEO

Impact of Verteporfin on HCC cells

2016-02-11 | GSE73396 | GEO

Exon arrays from HeLa cells transfected with RBM4-specific siRNA

Project description:RBM4 is a RNA-binding protein (RBP) able to modulate splicing by promoting exon inclusion and shares an import pathway with other splicing factors in the nucleus. In earlier studies we found that RBM4 interacts and colocalizes with WT1, which has been implicated in 10M-bM-^@M-^S15% of WilmsM-bM-^@M-^Y tumours and more recently in leukemya, is considered to be a tumour suppressor. RBM4, a RBP whose splicing effect is inhibited by the +KTS isoform of the tumour-suppressor/activator WT1, exhibits altered expression in different tumours, and may be essential for proliferation. Moreover, RBM4 binds to a number of RNAs of genes involved in acute myeloid leukaemia and cell cycle control. These results suggest that RBM4 may be involved in alternative splicing, tumorigenesis and particularly leukaemogenesis. To determine the endogenous transcripts that are targeted by RBM4 at the genome-wide level, we decided to perform exon microarray studies. RBM4-specific siRNA has been used for knockdown of RBM4 in HeLa cells. RNA was extracted using a Qiagen RNA extraction kit from untransfected, mock and siRNA-transfected HeLa cells and quality of RNA for microarray analysis was checked using a Bioanalyzer 2100 (Agilent Technologies). Experiments were run in triplicates.

2012-07-14 | E-GEOD-32933 | biostudies-arrayexpress

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