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

Guo, Peng-Da; Lu, Xing-Xing; Gan, Wen-Juan; Li, Xiuming; He, Xiaoshun; Zhang, Shen; Ji, Qinghua; Zhou, Feng; Cao, Yue; Wang, Jingru; Li, Jianming; Wu, Hua

doi:10.1158/0008-5472.can-15-2882

Cited by 48 publications

(41 citation statements)

References 54 publications

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“…1G). Further, we found that TPA was able to shuttle YAP from the nucleus, where YAP exerts its major function on tumorigenesis38, to the cytoplasm (Fig. 1H); these effects were also dose-dependent, suggesting YAP can be directly inhibited by TPA.…”

Section: Resultsmentioning

confidence: 81%

12-O-Tetradecanoylphorbol-13-acetate (TPA) is anti-tumorigenic in liver cancer cells via inhibiting YAP through AMOT

Zhu¹,

Chen²,

Zhang³

et al. 2017

Sci Rep

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TPA stimulates carcinogenesis in various types of cancers. However, we found that TPA inhibits transformative phenotypes in liver cancer cells via the translocation of YAP from the nucleus, where it functions as a transcriptional co-factor, to the cytoplasm. Such effects led to a separation of YAP from its dependent transcription factors. The inhibitory effects of TPA on YAP were AMOT dependent. Without AMOT, TPA was unable to alter YAP activity. Importantly, the depletion of YAP and AMOT blocked the TPA-reduced transformative phenotypes. In sum, TPA has been established as an anti-tumorigenic drug in liver cancer cells via YAP and AMOT.

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Section: Resultsmentioning

confidence: 81%

12-O-Tetradecanoylphorbol-13-acetate (TPA) is anti-tumorigenic in liver cancer cells via inhibiting YAP through AMOT

Zhu¹,

Chen²,

Zhang³

et al. 2017

Sci Rep

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“…Additionally, several studies have confirmed that the mRNA levels of Yap (and TAZ) sufciently correlate with target gene expression and are significantly associated with cancer progression [7, 23]. Meanwhile, an increasing number of studies have also shown that Yap has the ability to interact with tumor suppressors in the cytoplasm [52], supporting the idea that excessive expression of Yap is actually a more important factor in tumorigenesis regardless of Yap nuclear localization or cytoplasmic retention [7, 8]. …”

Section: Discussionmentioning

confidence: 99%

“…Yap has 504 amino acids (aa), including an N-terminal TEAD-binding domain (TBD, 48-102 aa), a WW domains (WW, 171-263 aa) and a C-terminal transcriptional activation domain (TAD, 292-488 aa) [38]. Therefore, three types of YAP mutants were constructed via base deletion to generate mutant-Yap (102-504 aa), which lacks the TBD, mutant-Yap (263-504 aa), which lacks the TBD and WW, and mutant-Yap (1-263 aa) , which lacks the TAD according to a previous study [8]. For lentiviral packaging, the three PCR-amplified mutant Yaps were cloned into pCMV vectors.…”

Section: Methodsmentioning

confidence: 99%

“…These malignancies are ascribed to accumulation of protein alterations, including dissemination of proto-oncogenes and loss or inactivation of tumor suppressor genes, which ultimately lead to tumor evolution and progression [2-6]. Furthermore, the increased survival and invasiveness of tumor cells are typical characteristics of RC [7, 8], suggesting a clinical need to abate excessive RC cell survival and migration.…”

Section: Introductionmentioning

confidence: 99%

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YAP Inhibits the Apoptosis and Migration of Human Rectal Cancer Cells via Suppression of JNK-Drp1-Mitochondrial Fission-HtrA2/Omi Pathways

Zhao

et al. 2017

Cell Physiol Biochem

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Background/Aims: The Hippo-Yap pathway is associated with tumor development and progression. However, little evidence is available concerning its role in cancer cell apoptosis and migration via mitochondrial homeostasis. Here, we identify mitochondrial fission as a regulator of the Hippo–Yap pathway in human rectal cancer tumorigenesis and metastasis. Methods: In this study, we performed loss-of function assays concerning Yap in RCC via shRNA. Cellular viability and apoptosis were measured via MTT, the TUNEL assay and trypan blue staining. Mitochondrial function was assessed via JC1 staining, the mPTP opening assay, mitochondrial respiratory function analysis, electron microscopy and immunofluorescence analysis of HtrA2/Omi. Mitophagy and mitochondrial fission were assessed via western blots and immunofluorescence. Cell migration was evaluated via the Transwell assay, wound-healing assay and immunofluorescence analysis of F-actin. The interaction between JNK and Yap was detected via co-immunoprecipitation and Yap recombinant mutagenic plasmid transfection. Western blots were used to analyze signaling pathways in conjunction with JNK inhibitors or HtrA2/Omi siRNA. Results: Yap is upregulated in human rectal cancer cells, where its expression correlates positively with cell survival and migration. Functional studies established that silencing of Yap drove JNK phosphorylation, which induced Drp1 activation and translocation to the surface of mitochondria, initiating mitochondrial fission. Excessive mitochondrial fission mediated HtrA2/Omi leakage from the mitochondria into the cytoplasm, where HtrA2/Omi triggered cellular apoptosis via the mitochondrial apoptosis pathway. Moreover, released HtrA2/Omi also phosphorylated cofilin and inhibited cofilin-mediated F-actin polymerization. F-actin collapse perturbed lamellipodia formation and therefore impaired cellular migration and invasion. Conclusion: Collectively, our results demonstrate that Hippo-Yap can serve as a tumor promoter in human rectal cancer and acts by restricting JNK/Drp1/mitochondrial fission/ HtrA2/Omi, with potential implications for new approaches to human rectal cancer therapy.

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“…18 Kaplan-Meier analysis, we indicated that nuclear YAP expression in the cancerous tissues correlated positively with lymph node metastasis, which might support the hypothesis that YAP can be used as a potential marker for tumor invasiveness. 23 We examined the expression levels of the WASF1 gene and found that they were downregulated following YAP knockdown In summary, we demonstrated that YAP was overexpressed in OSCC, notably in the nuclear region and that it promoted tumor migration and invasiveness. It is important to note that silencing of YAP was able to inactivate WAVE1, which reduced cell migration and invasion.…”

Section: Discussionmentioning

confidence: 84%

Yes‐associated protein promotes cell migration via activating Wiskott‐Aldrich syndrome protein family member 1 in oral squamous cell carcinoma

Shi

et al. 2019

J Oral Pathology Medicine

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Background: Yes-associated protein (YAP) is a candidate oncogene in various cancers including oral squamous cell carcinoma (OSCC). Our previous study demonstrated that TNF-alpha could inhibit cell proliferation and invasion by YAP phosphorylation in OSCC. However, the role of YAP in OSCC is not yet clear. The objective of the present study was to elucidate the function of YAP in promoting migration in OSCC and to explore the possible mechanism with a novel YAP inhibitor CA3.Methods: A total of 68 OSCC patients were enrolled, and the expression levels of YAP were investigated in tissue specimens by immunohistochemical staining. The inhibitory effects of CA3, a novel inhibitor of YAP, were demonstrated by immunofluorescence, Western blotting, and transwell assays. A human PCR motility array was performed to screen the changes in the gene expression profiles of the cells. In addition, shRNA interference, YAP re-expression, and WAVE1 overexpression plasmids were used to detect the regulatory mechanism of YAP and its relationship with cell migration.Results: Yes-associated protein nuclear expression levels were associated with metastasis and 5-year overall survival rate. CA3 exhibited potent inhibitory effects on OSCC migration. YAP knockdown significantly suppressed tumor cell migration in OSCC. These effects were rescued when YAP was re-expressed and during WAVE1 overexpression in YAP-shRNA stable cells. Conclusions:The present study revealed that YAP was associated with cell migration and that this process was regulated by YAP/WAVE1. We also demonstrated that CA3 exhibited marked inhibitory effects on YAP expression and that it could be considered a potential therapeutic target for the treatment of OSCC. K E Y W O R D Smigration, oral squamous cell carcinoma, WAVE1, yes-associated protein | 291 QI et al.

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

Cited by 48 publications

References 54 publications

12-O-Tetradecanoylphorbol-13-acetate (TPA) is anti-tumorigenic in liver cancer cells via inhibiting YAP through AMOT

12-O-Tetradecanoylphorbol-13-acetate (TPA) is anti-tumorigenic in liver cancer cells via inhibiting YAP through AMOT

YAP Inhibits the Apoptosis and Migration of Human Rectal Cancer Cells via Suppression of JNK-Drp1-Mitochondrial Fission-HtrA2/Omi Pathways

Yes‐associated protein promotes cell migration via activating Wiskott‐Aldrich syndrome protein family member 1 in oral squamous cell carcinoma

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