Hippo Coactivator YAP1 Upregulates SOX9 and Endows Esophageal Cancer Cells with Stem-like Properties

Song, Shumei; Ajani, Jaffer A.; Honjo, Soichiro; Maru, Dipen M.; Chen, Qiongrong; Scott, Ailing W.; Heallen, Todd R.; Xiao, Lianchun; Hofstetter, Wayne L.; Weston, Brian; Lee, Jeffrey H.; Wadhwa, Roopma; Sudo, Kazuki; Stroehlein, John R.; Martin, James F.; Hung, Mien‐Chie; Johnson, Randy L.

doi:10.1158/0008-5472.can-13-3569

Cited by 235 publications

(249 citation statements)

References 41 publications

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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%

“…and K.F.). Both the YAP staining intensity (a scale of from 0 to 3 was used, where 0 is negative, 1 is weak staining, 2 is moderate staining, and 3 is strong staining) and nuclear localization (the percentage of tumor cell nuclei stained, where 0 is no staining, 1 is Յ10% of tumor cell nuclei stained, 2 is 10 to 50% stained, and 3 is Ͼ50% stained) were scored (52).…”

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confidence: 99%

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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

142

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%

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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

142

151

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“…Thus, the YAP/TAZ-induced transcriptional program may influence tumor-initiating properties that are associated with aggressive OSCC. Additional transcription factors implicated in cancer progression were also regulated by YAP/TAZ, including SOX9, which has recently been described as a target of YAP in esophageal cancers (45). Notably, members of the TEAD family were induced by YAP/TAZ, and increased expression of TEAD4 was significantly elevated with increased OSCC grade and stage.…”

Section: Discussionmentioning

confidence: 99%

A YAP/TAZ-Regulated Molecular Signature Is Associated with Oral Squamous Cell Carcinoma

Hiemer

Zhang

Kartha

et al. 2015

Molecular Cancer Research

114

144

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Oral squamous cell carcinoma (OSCC) is a prevalent form of cancer that develops from the epithelium of the oral cavity. OSCC is on the rise worldwide, and death rates associated with the disease are particularly high. Despite progress in understanding of the mutational and expression landscape associated with OSCC, advances in deciphering these alterations for the development of therapeutic strategies have been limited. Further insight into the molecular cues that contribute to OSCC is therefore required. Here we show that the transcriptional regulators YAP (YAP1) and TAZ (WWTR1), which are key effectors of the Hippo pathway, drive pro-tumorigenic signals in OSCC. Regions of pre-malignant oral tissues exhibit aberrant nuclear YAP accumulation, suggesting that dysregulated YAP activity contributes to the onset of OSCC. Supporting this premise, we determined that nuclear YAP and TAZ activity drives OSCC cell proliferation, survival, and migration in vitro, and is required for OSCC tumor growth and metastasis in vivo. Global gene expression profiles associated with YAP and TAZ knockdown revealed changes in the control of gene expression implicated in pro-tumorigenic signaling, including those required for cell cycle progression and survival. Notably, the transcriptional signature regulated by YAP and TAZ significantly correlates with gene expression changes occurring in human OSCCs identified by “The Cancer Genome Atlas” (TCGA), emphasizing a central role for YAP and TAZ in OSCC biology.

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“…Profoundly, VP abrogates liver overgrowth induced by YAP over-expression in vivo, verifying the therapeutic potential of targeting YAP-TEAD interaction. More recently, it was demonstrated that VP inhibits esophageal cancer development in vivo by down-regulating SOX9, another YAP-TEAD target gene [108]. Simvastatin, which is originally prescribed to reduce cholesterol in patients with cardiovascular disease, is recently found to inhibit YAP-TEAD activity and leads to suppression of RHAMM transcription in breast cancer cells [107].…”

Section: Yap-targeted Cancer Therapymentioning

confidence: 99%

The regulation and function of YAP transcription co-activator

Zhu

Zhao

2015

ABBS

112

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The Hippo pathway was initially identified in Drosophila by genetic mosaic screens for tumor suppressor genes. Researches indicated that the Hippo pathway is a key regulator of organ size and is conserved during evolution. Furthermore, studies of mouse models and clinical samples demonstrated the importance of Hippo pathway dysregulation in human cancer development. In addition, the Hippo pathway contributes to progenitor cell and stem cell self-renewal and is thus involved in tissue regeneration. In the Hippo pathway, MST1/2 kinases together with the adaptor protein SAV phosphorylate LATS1/2 kinases. Interaction with an adaptor protein MOB is also important for LATS1/2 activation. Activated LATS1/2 in turn phosphorylate and inhibit Yes-associated protein (YAP). YAP is a key downstream effector of the Hippo pathway, and is a transcriptional co-activator that mainly interacts with TEAD family transcription factors to promote gene expression. Alteration of gene expression by YAP leads to cell proliferation, apoptosis evasion, and also stem cell amplification. In this review, we mainly focus on YAP, discussing its regulation and mechanisms of action in the context of organ size control, tissue regeneration and tumorigenesis.

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Hippo Coactivator YAP1 Upregulates SOX9 and Endows Esophageal Cancer Cells with Stem-like Properties

Cited by 235 publications

References 41 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

A YAP/TAZ-Regulated Molecular Signature Is Associated with Oral Squamous Cell Carcinoma

The regulation and function of YAP transcription co-activator

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