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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. 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).

ORGANISM(S): Homo sapiens

SUBMITTER: Zefeng Wang

PROVIDER: E-GEOD-80372 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.

2016-06-16 | GSE80372 | 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

Global microRNA expression analysis in mouse skin normal tissues and skin tumors induced by constitutive active YAP mutant.

Project description:Global downregulation of microRNAs (miRNAs) is commonly observed in human cancers and can have a causative role in tumorigenesis. The mechanisms responsible for this phenomenon remain poorly understood. Here we show that YAP, the downstream target of the tumor-suppressive Hippo signaling pathway regulates miRNA biogenesis in a cell density-dependent manner. At low cell density, nuclear YAP binds and sequesters p72 (DDX17), a regulatory component of the miRNA processing machinery. At high cell density, Hippo-mediated cytoplasmic retention of YAP facilitates p72 association with Microprocessor and binding to a specific sequence motif in pri-miRNAs. Inactivation of the Hippo pathway or expression of constitutively active YAP causes widespread miRNA suppression in cells and tumors and a corresponding post-transcriptional induction of MYC expression. Thus, the Hippo pathway links contact-inhibition regulation to miRNA biogenesis and may be responsible for the widespread miRNA repression observed in cancer. Two conditions (normal epidermal cells and oncogenic epidermal cells expressing YAP S127A mutant) were analyzed in duplicate.

2014-03-03 | E-GEOD-52206 | biostudies-arrayexpress

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

Switch Enhancer Elements Control Cell Fate in Human Embryonic Stem Cells (ChIP-Seq)

Project description:A small toolkit of morphogens is used repeatedly to direct development, raising the question of how context dictates interpretation of the same cue. One example is the TGFβ pathway that in human embryonic stem cells fulfills two opposite functions: pluripotency maintenance and mesendoderm (ME) specification. Using proteomics coupled to analysis of genome occupancy, we uncover a regulatory complex comprised of transcriptional effectors of the Hippo pathway (TAZ/YAP/TEAD), the TGFβ pathway (SMAD2/3) and the pluripotency regulator OCT4 (TSO). TSO collaborates with NuRD repressor complexes to buffer pluripotency gene expression, while suppressing ME genes. Importantly, the SMAD DNA binding partner FOXH1, a major specifier of ME, is found near TSO elements and upon fate specification we show that TSO is disrupted with subsequent SMAD-FOXH1 induction of ME. These studies define switch enhancer elements and provide a framework to understand how cellular context dictates interpretation of the same morphogen signal in development. ChIP experiment, a total of 8 samples: 4 samples DMSO treated (Input ctr, IgG ctr, SMAD2 precipitation, TEAD4 precipitation), 4 samples SB431542 (Input ctr, IgG ctr, SMAD2 precipitation, TEAD4 precipitation)

2013-12-18 | E-GEOD-52437 | biostudies-arrayexpress

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 10–15% of Wilms’ 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.

2012-07-15 | GSE32933 | GEO

YAP Inhibition in HCC cells (Hep3B)

Project description:siRNA-mediated inhibition compared to untreated cells and cells transfected with nonsense siRNA. Loss of contact inhibition and anchorage-independent growth are hallmarks of cancer cells. In this context, frequent inactivation of the Hippo pathway and subsequent nuclear enrichment of the transcriptional coactivator yes-associated protein (YAP) uncouple cell proliferation and anti-apoptosis from contact inhibition, associated with uncontrolled tumor growth and tumor cell dissemination. However, general molecular mechanisms of tumor-supporting YAP activity remain unclear. In this study, we show that overexpression and nuclear accumulation of YAP in hepatocytes and hepatocellular carcinoma (HCC) cells leads to an induction of the Notch pathways through transcriptional activation of the Notch ligand jagged-1 (Jag-1). This induction of Jag-1 strictly depends on binding of YAP to TEAD4 and does not rely on WNT/β-catenin pathway activity. Co-activation of YAP, TEAD4, Jag-1, and the Notch target gene Hes-1 was significantly higher in HCC from patients with poor prognosis. High-level expression and nuclear accumulation of YAP correlates with Jag-1/Notch activation not only in human HCC tissues, but also in colon and pancreatic cancer tissues. Thus, our data demonstrate that YAP-driven co-activation of the Jag-1/Notch pathway in part facilitates oncogenic properties of the oncogene YAP not only in HCC but also in different gastrointestinal malignancies. Expression profiling of untreated HCC cell lines (control 1), cells transfected with scrambled/nonsense siRNA (control 2), and after siRNA-mediated YAP inhibition.

2012-11-01 | E-GEOD-35004 | biostudies-arrayexpress

Gene expression profiling of effect of Yap inhibition in a genetically engineered mouse model of hepatocellular carcinoma

Project description:Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC). Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis. We show that YAP functions as a rheostat maintaining metabolic specialization, differentiation and quiescence within the hepatocyte compartment. Importantly, treatment with siRNA-lipid nanoparticles (siRNA-LNPs) targeting YAP restores hepatocyte differentiation and causes pronounced tumor regression in a genetically engineered mouse HCC model (mice with liver-specific Mst1/Mst2 double knockout). Furthermore, YAP targets are enriched in an aggressive human HCC subtype characterized by a proliferative signature and absence of CTNNB1 mutations. Thus, our work reveals Hippo signaling as a key regulator of positional identity of hepatocytes, supports targeting YAP using siRNA-LNPs as a paradigm of differentiation-based therapy, and identifies an HCC subtype potentially responsive to this approach. Mice with liver-specific Mst1/Mst2 double-knockout (Adeno-Cre injected Mst1-/-; Mst2Flox/Flox mice) were monitored for the formation of HCC by ultrasound imaging. Animals were then randomized to be treated by intravenous injection of either siYap-LNPs or siLuciferase-LNPs for a period of 9 days.

2015-03-07 | E-GEOD-65665 | biostudies-arrayexpress

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