YAP oncogene overexpression supercharges colon cancer proliferation

Avruch, Joseph; Zhou, Dawang; Bardeesy, Nabeel

doi:10.4161/cc.11.6.19453

Cited by 112 publications

(113 citation statements)

References 80 publications

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“…Studies have demonstrated that YAP was overexpressed in human colon cancer specimens and cell lines. Overexpression of YAP promoted the growth and survival of colon cancer cells, which was indicative of its oncogenic function and suggested that its overexpression is a substantial contributor in cancer development (8)(9)(10). In addition, studies have confirmed that TAZ is upregulated in CRC and has an important role in CRC progression via promoting cell proliferation and survival (11)(12)(13).…”

Section: Introductionmentioning

confidence: 90%

Upregulation of Yes-associated protein and transcriptional co-activator with PDZ-binding motif influences the behavior of LOVO human colon adenocarcinoma cells

Liu

Lan

Zhu

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. The present study aimed to investigate the role of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) in the LOVO human colon adenocarcinoma cell line and explore the underlying mechanisms. First, the expression levels of YAP and TAZ were detected in LOVO cells using reverse-transcription quantitative PCR, and the results suggested that YAP and TAZ were faintly expressed in LOVO cells. To investigate the exact role of YAP and TAZ in LOVO cells, stable YAP-and/or TAZ-overexpressing LOVO cell lines were established using YAP and/or TAZ expression plasmids. An MTT assay and flow cytometry were used to assess cell proliferation and apoptosis, respectively. The results indicated that compared with the control, YAP or TAZ overexpression significantly increased the proliferation ability of LOVO cells, while apoptosis was significantly decreased. Furthermore, the expression of the tumor-associated proteins connective tissue growth factor and cysteine-rich angiogenic inducer 61, which have critical roles in facilitating cancer cell proliferation, migration and invasion, were found to be upregulated following upregulation of YAP and TAZ. In addition, the expression of cell apoptosis-associated protein B-cell lymphoma 2 (Bcl-2) was significantly increased, while Bcl-2-associated X protein and caspase-3 were inhibited by YAP or TAZ overexpression. All of these effects were amplified when YAP and TAZ were co-overexpressed. In conclusion, YAP and TAZ function as tumor promoters in human colon carcinoma, and upregulation of YAP and TAZ influences the behavior of LOVO colon adenocarcinoma cells via regulating tumor-associated gene expression.

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Section: Introductionmentioning

confidence: 90%

Upregulation of Yes-associated protein and transcriptional co-activator with PDZ-binding motif influences the behavior of LOVO human colon adenocarcinoma cells

Liu

Lan

Zhu

et al. 2017

Experimental and Therapeutic Medicine

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“…These observations are compatible with the idea that Yap acts as an oncogenic regulator for cancer development. Increased expression and activity of Yap is associated with the growth, metastatic potential, and poor prognosis of several cancer types, including liver cancer and colorectal cancer (19,24,50).…”

Section: Discussionmentioning

confidence: 99%

RARγ Downregulation Contributes to Colorectal Tumorigenesis and Metastasis by Derepressing the Hippo–Yap Pathway

Guo

Gan

et al. 2016

Cancer Research

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The Hippo-Yap pathway conveys oncogenic signals, but its regulation during cancer development is not well understood. Here, we identify the nuclear receptor RARg as a regulator of the Hippo-Yap pathway in colorectal tumorigenesis and metastasis. RARg is downregulated in human colorectal cancer tissues, where its expression correlates inversely with tumor size, TNM stage, and distant metastasis. Functional studies established that silencing of RARg drove colorectal cancer cell growth, invasion, and metastatic properties both in vitro and in vivo. Mechanistically, RARg controlled Hippo-Yap signaling to inhibit colorectal cancer development, acting to promote phosphorylation and binding of Lats1 to its transcriptional coactivator Yap and thereby inactivating Yap target gene expression. In clinical specimens, RARg expression correlated with overall survival outcomes and expression of critical Hippo-Yap pathway effector molecules in colorectal cancer patients. Collectively, our results defined RARg as tumor suppressor in colorectal cancer that acts by restricting oncogenic signaling by the Hippo-Yap pathway, with potential implications for new approaches to colorectal cancer therapy.Cancer Res; 76(13); 3813-25. Ó2016 AACR.

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“…The latter was initially described in drosophila for its ability to control organ size (19). Its role in EMT was demonstrated by studies in which nonphosphorylated (active) Hippo transducers YAP, TAZ, and TEAD were found to act either together, in conjunction with b-catenin/TCF, or with Smads (20,21) to induce genes that regulate cell morphology, migration, and cancer metastasis. Phosphorylation (inactivation) of the Hippo transducers is carried out by upstream kinases (Mst/Lats) resulting in their cytoplasmic retention and either proteasomal degradation (22) by the GSK3-b-associated degradation complex or sequestration of b-catenin and Smads thereby inhibiting the trans-activation of these transcription factors (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-β, and Wnt Signaling Pathways

Basu

Lettan

Damodaran

et al. 2014

Molecular Cancer Therapeutics

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Embryonic signaling pathways, in particular those mediated by Wnt and TGF-b, are known to play key roles in tumor progression through the induction of epithelial-mesenchymal transition (EMT). Their simultaneous targeting could therefore represent a desirable anticancer strategy. On the basis of recent findings that both Wnt and TGF-b-associated pathways are regulated by Hippo signaling in mammalian cells, we reasoned that targeting the latter would be more effective in inhibiting EMT. In a search for such inhibitors, we identified a small molecule (C19) with remarkable inhibitory activity not only against Hippo, but also against Wnt and TGF-b pathways. C19 inhibited cancer cell migration, proliferation, and resistance to doxorubicin in vitro, and exerted strong antitumor activity in a mouse tumor model. Mechanistically, C19 induced GSK3-b-mediated degradation of the Hippo transducer TAZ, through activation of the Hippo kinases Mst/Lats and the tumor suppressor kinase AMPK upstream of the degradation complex. Overall, this study identified C19 as a multi-EMT pathway inhibitor with a unique mechanism of action. The findings that both AMPK and Mst/Lats mediate the antitumor activity of C19 shed light on a potential cross-talk between metabolic and organ size control pathways in regulating cancer progression. By simultaneously targeting these two pathways, C19 may represent a new type of agents to suppress cancer progression and/or its recurrence.

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YAP oncogene overexpression supercharges colon cancer proliferation

Cited by 112 publications

References 80 publications

Upregulation of Yes-associated protein and transcriptional co-activator with PDZ-binding motif influences the behavior of LOVO human colon adenocarcinoma cells

Upregulation of Yes-associated protein and transcriptional co-activator with PDZ-binding motif influences the behavior of LOVO human colon adenocarcinoma cells

RARγ Downregulation Contributes to Colorectal Tumorigenesis and Metastasis by Derepressing the Hippo–Yap Pathway

Identification, Mechanism of Action, and Antitumor Activity of a Small Molecule Inhibitor of Hippo, TGF-β, and Wnt Signaling Pathways

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