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JOSD1 facilitates colorectal cancer progression via stabilizing YAP

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE256276 | GEO | 2024/09/11

REPOSITORIES: GEO

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DUB1 suppresses Hippo signaling via modulating TAZ protein in gastric cancer

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

OTUB1 promotes gastric cancer proliferation through regulating Hippo signaling pathway

Project description:Gastric cancer is still one of the most common cancer types and third leading cause of cancer deaths worldwide. Recent studies have showed that the Hippo signaling pathway plays a critical role in progression of gastric cancer. It is of great importance to demonstrate the regulation of Hippo signaling pathway and the degradation of YAP protein in gastric cancer. In this study, we found that OTUB1 is a critical factor to facilitate gastric cancer cell stemness and progression, which deubiquitinated and stabilized YAP protein.

2022-02-24 | GSE197135 | GEO

Regulation of Hippo/YAP axis by CXCR7 in the tumorigenesis of gastric cancer

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

Expression profile of osteosarcoma cells in which Sox2 maintains cancer stem cells

Project description:Sox2 is required to maintain osteosarcoma cell tumor initiation.Knockdown of Sox2 leads tpo loss of tumorigenic properties. To examine gene expression changes upon Sox2 knockdown, we performed microarray analysis on mouse osteosarcoma cells expressing scrambled or Sox2shRNA. We found that genes upregulated upon Sox2 knockdown included osteoblast diffrentiation genes and genes down regulated included cell cycle and RNA processing genes as well as YAP-TEAD target genes. The Hippo pathway has a profound tumor suppressive role in cancer by restraining the strong growth-promoting function of YAP. We have previously shown that the stem cell transcription factor Sox2 maintains the tumorigenicity of osteosarcoma cancer stem cells (CSCs). In this report, we describe that Sox2 maintains stemness by antagonizing the Hippo pathway via direct repression of Hippo activators, Nf2 (Merlin) and WWC1 (Kibra), thereby leading to exaggerated YAP function. YAP is potently oncogenic in osteosarcoma and its depletion sharply reduces the tumorigenic CSC fraction. Low Nf2, low WWC1, and high YAP expression mark the CSC fraction of the tumor population, while the more differentiated fraction has high Nf2, high WWC1 and reduced YAP expression. This Sox2-Hippo axis is conserved and also operates in other Sox2-dependent cancers such as glioblastomas. We propose that disruption of YAP transcriptional activity reduces CSCs and could be a therapeutic strategy for Sox2- dependent tumors. Gene expression of 482 mouse lines mOS482 were analyzed by microarray. 3 replicates each of scrambled and Sox2shRNA were processed and hybridized

2015-02-15 | E-GEOD-64965 | biostudies-arrayexpress

Transcriptional targets of Hippo signaling in mammalian cells

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

RBCK1 is an Endogenous Inhibitor for Triple Negative Breast Cancer via Hippo/YAP axis

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

Regenerative reprogramming of the intestinal stem cell state via Hippo signaling suppresses metastatic colorectal cancer [Organoid_RNAseq]

Project description:Although the Hippo transcriptional coactivator YAP is considered oncogenic in many tissues, its roles in intestinal homeostasis and colorectal cancer (CRC) remain controversial. Here, we demonstrate that the Hippo kinases LATS1/2 and MST1/2, which inhibit YAP activity, are required for maintaining Wnt signaling and canonical stem cell function. Hippo inhibition induces a distinct epithelial cell state marked by low Wnt signaling, a wound-healing response, and transcription factor Klf6 expression. Notably, loss of LATS1/2 or overexpression of YAP is sufficient to reprogram Lgr5+ cancer stem cells to this state and thereby suppress tumor growth in organoids, patient-derived xenografts, and mouse models of primary and metastatic CRC. Finally, we demonstrate that genetic deletion of YAP and its paralog TAZ promotes the growth of these tumors. Collectively, our results establish the role of YAP as a tumor suppressor in the adult colon and implicate Hippo kinases as therapeutic vulnerabilities in colorectal malignancies.

2020-06-24 | GSE152374 | GEO

Regenerative reprogramming of the intestinal stem cell state via Hippo signaling suppresses metastatic colorectal cancer [LATS_scRNAseq]

2020-06-24 | GSE152370 | GEO

Regenerative reprogramming of the intestinal stem cell state via Hippo signaling suppresses metastatic colorectal cancer [DSS_scRNAseq]

2020-06-24 | GSE152369 | GEO

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

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