Mutant Gq/11 Promote Uveal Melanoma Tumorigenesis by Activating YAP

Yu, Fa‐Xing; Luo, Jing; Mo, Jung-Soon; Liu, Guangbo; Kim, Young Chul; Meng, Zhipeng; Zhao, Ling; Peyman, Gholam A.; Ouyang, Hong; Jiang, Wei; Zhao, Jiaxin; Chen, Xu; Zhang, Liangfang; Wang, Cun‐Yu; Bastian, Boris C.; Zhang, Kang; Guan, Kun‐Liang

doi:10.1016/j.ccr.2014.04.017

Cited by 390 publications

(426 citation statements)

References 34 publications

(60 reference statements)

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“…Indeed, Liu-Chittenden et al screened a small-molecule library (consisting of 3,300 FDA-approved drugs) for agents that inhibit YAP-TEAD activity in a cell-based assay (72). Verteporfin was identified to be a compound effective at preventing hepatic tumorigenesis driven by YAP overexpression (72) and the growth of xenograft tumors in immunodeficient mice (52,74). Thus, administration of verteporfin is an effective pharmacologic approach to inhibit YAP signaling, and these studies strongly support the feasibility of targeting YAP in human cancer in which Hippo-YAP is deregulated.…”

Section: Discussionmentioning

confidence: 99%

The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

Zhang¹,

Yang²,

Chen³

et al. 2015

Molecular and Cellular Biology

137

151

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f Yes-associated protein (YAP) is an effector of the Hippo tumor suppressor pathway. The functional significance of YAP in prostate cancer has remained elusive. In this study, we first show that enhanced expression of YAP is able to transform immortalized prostate epithelial cells and promote migration and invasion in both immortalized and cancerous prostate cells. We found that YAP mRNA was upregulated in androgen-insensitive prostate cancer cells (LNCaP-C81 and LNCaP-C4-2 cells) compared to the level in androgen-sensitive LNCaP cells. Importantly, ectopic expression of YAP activated androgen receptor signaling and was sufficient to promote LNCaP cells from an androgen-sensitive state to an androgen-insensitive state in vitro, and YAP conferred castration resistance in vivo. Accordingly, YAP knockdown greatly reduced the rates of migration and invasion of LNCaP-C4-2 cells and under androgen deprivation conditions largely blocked cell division in LNCaP-C4-2 cells. Mechanistically, we found that extracellular signal-regulated kinase-ribosomal s6 kinase signaling was downstream of YAP for cell survival, migration, and invasion in androgen-insensitive cells. Finally, immunohistochemistry showed significant upregulation and hyperactivation of YAP in castration-resistant prostate tumors compared to their levels in hormone-responsive prostate tumors. Together, our results identify YAP to be a novel regulator in prostate cancer cell motility, invasion, and castration-resistant growth and as a potential therapeutic target for metastatic castration-resistant prostate cancer (CRPC). P rostate cancer is the most common malignancy and the second leading cause of cancer-related mortality among men in the United States (1). Although androgen deprivation therapy (through medical or surgical castration) is highly effective for advanced prostate cancer (1, 2), the majority of patients eventually develop resistance and progress to castration-resistant prostate cancer (CRPC). Unfortunately, most cases of CRPC are currently incurable (1). The cause of castration resistance is still not completely known. It is expected that understanding the molecular mechanisms and identifying the molecular pathways underlying the acquisition of castration resistance in prostate cancer are critical for the design of therapeutic strategies and may lead to the discovery of novel targets.The Hippo signaling pathway, originally defined by fly geneticists, plays an important role in tumorigenesis by regulating cell proliferation and apoptosis (3-7). In mammals, protein kinases Mst1/2 (mammalian sterile 20-like 1 and 2) and Lats1/2 (large tumor suppressor 1 and 2) and the adaptor proteins WW45 (WW domain-containing protein) and Mob1 (Mps one binder 1) are the Hippo core components. These proteins form complexes to regulate their activity mainly through phosphorylation. The Hippo core is tumor suppressive and exerts its function by phosphorylating and inactivating YAP (Yes-associated protein) and its paralog, TAZ (transcriptional coactivator with a PDZ-bi...

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Section: Discussionmentioning

confidence: 99%

The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

Zhang¹,

Yang²,

Chen³

et al. 2015

Molecular and Cellular Biology

137

151

View full text Add to dashboard Cite

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“…Therefore, depending on the nature of downstream G proteins, GPCRs can either activate or inhibit the LATS kinase to stimulate or suppress YAP activity. Elevated GPCR expression or mutation of Gα proteins leads to aberrant YAP activation and exhibits strong disease implications Yu et al 2014;Liu et al 2015;Zhou et al 2015a). For example, estrogen acts through G protein-coupled estrogen receptor (GPER) to inhibit LATS and activate YAP/TAZ, indicating a possible role of YAP/TAZ activation by estrogen in breast cancer (Zhou et al 2015a).…”

Section: Soluble Factors and G-protein-coupled Receptors (Gpcrs)mentioning

confidence: 99%

“…Both basic and clinical cancer research has implicated a role of YAP and TAZ in cancer initiation and development through suppressing cell apoptosis and promoting cell prolifieration (Moroishi et al 2015a). Concordantly, YAP and TAZ have been considered as therapeutic targets for a number of cancers (Liu-Chittenden et al 2012;Jiao et al 2014;Yu et al 2014;Zhou et al 2015b) as well as several other diseases . Notably, the R331W missense mutation of YAP has recently been linked to a germline risk in lung adenocarcinoma (Chen et al 2015a).…”

Section: The Yap/taz Transcriptional Programs and Their Functional Oumentioning

confidence: 99%

Mechanisms of Hippo pathway regulation

2016

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The Hippo pathway was initially identified in Drosophila melanogaster screens for tissue growth two decades ago and has been a subject extensively studied in both Drosophila and mammals in the last several years. The core of the Hippo pathway consists of a kinase cascade, transcription coactivators, and DNA-binding partners. Recent studies have expanded the Hippo pathway as a complex signaling network with >30 components. This pathway is regulated by intrinsic cell machineries, such as cell–cell contact, cell polarity, and actin cytoskeleton, as well as a wide range of signals, including cellular energy status, mechanical cues, and hormonal signals that act through G-protein-coupled receptors. The major functions of the Hippo pathway have been defined to restrict tissue growth in adults and modulate cell proliferation, differentiation, and migration in developing organs. Furthermore, dysregulation of the Hippo pathway leads to aberrant cell growth and neoplasia. In this review, we focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in the regulation and function of the Hippo pathway.

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“…Human melanocyte cell lines expressing GNAQ Q209L exhibit activated YAP within the Hippo tumor suppressor pathway (12,13). Yap activation can be detected by examining the amount of Yap in the cell nucleus, where it is translocated upon phosphorylation.…”

Section: Mitf-crementioning

confidence: 99%

“…The function of Gaq/11 is to link various 7 transmembrane G protein-coupled receptors (GPCR) to downstream signaling effectors inside cells, canonically phospholipase C (9). Q209 and R183 mutations also activate the MAPK pathway and the Hippo tumor suppressor pathway (2,3,(11)(12)(13). During signaling, GDP-bound alpha subunits are stimulated by ligand binding to GPCRs, which causes the alpha subunits to release GDP, bind GTP, and assume the active conformation that can interact with downstream effectors.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic G Protein GNAQ Induces Uveal Melanoma and Intravasation in Mice

2015

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GNAQ and GNA11 are heterotrimeric G protein alpha subunits, which are mutated in a mutually exclusive pattern in most cases of uveal melanoma, one of the most aggressive cancers. Here we introduce the first transgenic mouse model of uveal melanoma, which develops cancers induced by expression of oncogenic GNAQ Q209L under control of the Rosa26 promoter. Disease penetrance is 100% by 3 months of age, with 94% of mice also developing lung tumors. In this model, the Yap protein of the Hippo pathway is activated in the eyes, and blood vessels near the lesions in the head and lungs exhibit melanocytic invasion. While full transcription levels are not necessary for GNAQ Q209L to transform mouse melanocytes, we obtained suggestive evidence of a selective advantage for increased GNAQ Q209L expression in human tumors. Intriguingly, enforced expression of GNAQ Q209L progressively eliminated melanocytes from the interfollicular epidermis in adults, possibly explaining the near absence of GNAQ Q209 mutations in human epithelial melanomas. The mouse model also exhibited dermal nevi and melanocytic neoplasms of the central nervous system, accompanied by impaired hearing and balance, identifying a novel role for GNAQ in melanocyte-like cells of the inner ear. Overall, this model offers a new tool to dissect signaling by oncogenic GNAQ and to test potential therapeutics in an in vivo setting where GNAQ Q209L mutations contribute to both the initiation and metastatic progression of uveal melanoma. Cancer Res; 75(16); 3384-97. Ó2015 AACR.

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Mutant Gq/11 Promote Uveal Melanoma Tumorigenesis by Activating YAP

Cited by 390 publications

References 34 publications

The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

Mechanisms of Hippo pathway regulation

Oncogenic G Protein GNAQ Induces Uveal Melanoma and Intravasation in Mice

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