OTUB1 promotes gastric cancer proliferation through regulating Hippo signaling pathway
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE197135 | GEO | 2022/02/24
REPOSITORIES: GEO
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Project description:The Hippo pathway functions as a tumor-suppressor pathway in human cancers, while the dys-function of Hippo pathway is frequently observed in malignancies. Although the YAP/TAZ activity is tightly controlled by the phosphorylation cascade of MST-LATS-YAP/TAZ axis, it is still unclear why YAP/TAZ protein is activated in human cancers, even Hippo pathway is still active. Besides phosphorylation, recent studies implicate that several post-translational modifications also play critical roles in modulating TAZ function, including ubiquitination. Here, by a DUB (Deubiquitinases) siRNA screening library, we discovered DUB1 as a critical modulator to facilitate gastric cancer stemness and progression, which deubiquitinated and activated TAZ protein. We also identified DUB1 was elevated in gastric cancer, which correlated with TAZ activation and poor survival. DUB1 associated with TAZ protein and deubiquitinated TAZ at several lysine sites, which subsequently stabilized and facilitated TAZ function. Our study revealed a novel deubiquitinase of Hippo/TAZ axis and one possible therapeutic target for Hippo-driven gastric cancer.
2022-02-12 | GSE196262 | GEO
Project description:The Hippo pathway is crucial in organ size control and tumorigenesis. The dys-regulation of Hippo/YAP axis is vastly observed in gastric cancer, while the effective therapeutic targets for Hippo/YAP axis are still not clear. It is important and urgent to identify reliable drug targets and the underlying mechanisms, which could inhibit the activity of Hippo/YAP axis and gastric cancer progression. In our current study, we demonstrate the membrane receptor CXCR7 (C-X-C chemokine receptor 7) is an important modulator for Hippo/YAP axis. The activation of CXCR7 could stimulate gastric cancer cell progression through Hippo/YAP axis in vitro and in vivo, while pharmaceutical inhibition of CXCR7 via ACT-1004-1239 could block the tumorigenesis in gastric cancer. Molecular studies reveal that the activation of CXCR7 could dephosphorylate YAP, facilitate YAP nuclear accumulation and transcriptional activation in gastric cancer. CXCR7 functions via G-protein Gαq/11 and Rho GTPase to activate YAP activity. Interestingly, ChIP assay shows that YAP could bind to the promoter region of CXCR7 and facilitate its gene transcription, which indicates CXCR7 is both the upstream signaling and downstream target for Hippo/YAP axis in gastric cancer. In general, we identified a novel positive feedback loop between CXCR7 and Hippo/YAP axis, while blockade of CXCR7 could be a plausible strategy for gastric cancer.
2023-11-15 | GSE233094 | GEO
Project description:Colorectal cancer is one of the most lethal human malignancies in the world. Although great efforts are put in developing novel therapeutic targets, the effective targeting drugs are still limited. Recent studies reveal the abnormality of Hippo/YAP axis play critical role in the oncogenic process of Colorectal cancer. It is of great importance to demonstrate the regulation of Hippo signaling activity and YAP protein turnover in Colorectal cancer. Besides, the phosphorylation cascade on YAP function, which has been thoroughly investigated, the ubiquitination of YAP is also important in Hippo signaling status. Here, We utilized the DUB (Deubiquitinase) siRNA library to identify critical DUB for Hippo signaling. We discovered JOSD1 as a critical factor to facilitate Colorectal cancer cell stemness and progression, which deubiquitinated and stabilized YAP protein. The clinical data analysis implicated JOSD1 was correlated with YAP activity and poor survival. Molecular studies demonstrated that JOSD1 associated with the YAP protein and enhanced YAP protein stability by blocking the K48-linked polyubiquitination of YAP. Our study revealed a novel deubiquitinase of Hippo/YAP axis and one possible therapeutic target for YAP-driven Colorectal cancer
2024-09-11 | GSE256276 | GEO
Project description:The Hippo pathway is an emerging signaling cascade involved in the regulation of organ size control. It consists of evolutionally conserved protein kinases that are sequentially phosphorylated and activated. The active Hippo pathway subsequently phosphorylates a transcription coactivator, YAP, which precludes its nuclear localization and transcriptional activation. Identification of transcriptional targets of YAP in diverse cellular contexts is therefore critical to the understanding of the molecular mechanisms in which the Hippo pathway restricts tissue growth. We used microarrays to profile the gene expression patterns upon acute siRNA knockdown of Hippo pathway components in multiple mammalian cell lines and identified a set of genes representing immediate transcriptional targets of the Hippo/Yap signaling pathway. Three mammalian cell lines (HEK293T, HepG2, HaCaT) were transfected with scramble siRNA controls or siRNAs against NF2 and LATS2, two core components of the Hippo pathway, simultaneously. Total RNAs were harvested four days after transfection to reveal the gene expression pattern unsing microarry. YAP and TAZ siRNAs were also transfected along with NF2 and LATS2 siRNAs to identify YAP/TAZ-dependent transcriptional targets upon loss of NF2/LATS2.
2013-12-31 | E-GEOD-49384 | biostudies-arrayexpress
Project description:Triple negative breast cancer (TNBC) is one of the most lethal breast cancer subtypes. Due to a lack of effective therapeutic targets, chemotherapy is still the main medical treatment for TNBC patients. Thus, it is important and necessary to identify novel therapeutic targets for TNBC. Recent genomic studies implicated the hyper-activation of Hippo/YAP signaling in TNBC, manifesting its critical roles in TNBC carcinogenesis and cancer progression. RBCK1 was firstly identified as an important component for linear ubiquitin assembly complex (LUBAC) and facilitates NFKB signaling in immune response. Further studies showed RBCK1 also facilitated luminal type breast cancer growth and endocrine resistance via trans-activation estrogen receptor alpha. Interestingly, our data revealed an opposite function for RBCK1 in TNBC progression. RBCK1 over-expression inhibited TNBC cell progression in vitro and in vivo, while RBCK1depletion promoted TNBC cell invasion. The whole genomic expression profiling showed that RBCK1 depletion activated Hippo/YAP axis. RBCK1 depletion increased YAP protein level and Hippo target gene expression in TNBC. The molecular biology studies showed that RBCK1 could associate with YAP protein and enhance YAP protein stability via promoting YAP K48-linked poly-ubiquitination at several YAP lysine sites (K76, K204 and K321). Our study revealed the multi-faced RBCK1 function in different subtypes of breast cancer patients and a promising therapeutic target for TNBC treatment.
2022-02-05 | GSE195712 | GEO
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
Project description:The Hippo pathway is an emerging signaling cascade involved in the regulation of organ size control. It consists of evolutionally conserved protein kinases that are sequentially phosphorylated and activated. The active Hippo pathway subsequently phosphorylates a transcription coactivator, YAP, which precludes its nuclear localization and transcriptional activation. Identification of transcriptional targets of YAP in diverse cellular contexts is therefore critical to the understanding of the molecular mechanisms in which the Hippo pathway restricts tissue growth. We used microarrays to profile the gene expression patterns upon acute siRNA knockdown of Hippo pathway components in multiple mammalian cell lines and identified a set of genes representing immediate transcriptional targets of the Hippo/Yap signaling pathway.
2013-12-31 | GSE49384 | GEO
Project description:The Hippo pathway plays a key role in development, organ size control, and tissue homeostasis, and its dysregulation contributes to cancer. The LATS tumor suppressor kinases phosphorylate and inhibit the YAP/TAZ transcriptional co-activators to suppress gene expression and cell growth. Through a screen of marine natural products, we identified microcolin B (MCB) as a Hippo activator. Structure-activity optimization yielded more potent MCB analogs, which led to identification of PITP as the direct molecular targets. We established a critical role of PITP in regulating LATS and YAP. Moreover, we showed that PITP influences the Hippo pathway via cellular PI4P. This study uncovers a previously unrecognized role of PITP in Hippo pathway regulation and as potential cancer therapeutic targets.
2022-03-20 | GSE198890 | GEO
Project description:YAP is a transcriptional co-activator of the hippo signaling pathway and is known for its oncogenic and regenerative activity across numerous tissue types. In particular, high YAP levels in patients with gastric cancer (GC) confer a lower survival rate and poor prognosis for these individuals. Therefore, there is a great need to develop targeted therapies against these aggressive tumors. However, the role of YAP and its underlying molecular mechanisms during gastric tumorigenesis are still poorly understood. Using genetic models, we demonstrate the oncogenic function of YAP in CLU+ gastric cells in vivo. YAP over-expression in CLU+ cells induced atrophy, metaplasia and hyperproliferation in the gastric corpus, while its deletion in a Notch activated gastric tumor model rescued metaplasia. Furthermore, we defined the YAP1 targetome in YAP activated gastric tumors, and showed that YAP1 binds to the active chromatin elements of spasmolytic polypeptide-expressing metaplasia (SPEM) related genes and activates their expressions in gastric tumors and ulcers. Together, these results reveal YAP1 as a critical regulator of metaplasia in the gastric corpus, and highlights YAP signaling as a possible therapeutic target to inhibit the progression of gastric tumors.
2023-11-07 | GSE199171 | GEO
Project description:YAP is a transcriptional co-activator of the hippo signaling pathway and is known for its oncogenic and regenerative activity across numerous tissue types. In particular, high YAP levels in patients with gastric cancer (GC) confer a lower survival rate and poor prognosis for these individuals. Therefore, there is a great need to develop targeted therapies against these aggressive tumors. However, the role of YAP and its underlying molecular mechanisms during gastric tumorigenesis are still poorly understood. Using genetic models, we demonstrate the oncogenic function of YAP in CLU+ gastric cells in vivo. YAP over-expression in CLU+ cells induced atrophy, metaplasia and hyperproliferation in the gastric corpus, while its deletion in a Notch activated gastric tumor model rescued metaplasia. Furthermore, we defined the YAP1 targetome in YAP activated gastric tumors, and showed that YAP1 binds to the active chromatin elements of spasmolytic polypeptide-expressing metaplasia (SPEM) related genes and activates their expressions in gastric tumors and ulcers. Together, these results reveal YAP1 as a critical regulator of metaplasia in the gastric corpus, and highlights YAP signaling as a possible therapeutic target to inhibit the progression of gastric tumors.
2023-11-07 | GSE199170 | GEO