Suppression of YAP by DDP disrupts colon tumor progression

Li, Kun; Guo, Jiwei; Wu, Yan; Jin, Dayong; Jiang, Hong; Liu, Chengxia; Qin, Chengyong

doi:10.3892/or.2018.6297

Cited by 10 publications

(10 citation statements)

References 35 publications

(28 reference statements)

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“…8 The diagram of ALKBH5 inhibits NSCLC growth and metastasis by regulating YAP expression and activity transduction, organ generation, stem cell self-renewal, and organ volume [22]. Therefore, this signaling pathway has attracted increasing interest in the scientific community [45,46]. Several key proteins in the MST/Hippo signaling pathway participate in tumor formation and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

m6A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2–mediated YAP activity in NSCLC

et al. 2020

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Background: The importance of mRNA methylation erased by ALKBH5 in mRNA biogenesis, decay, and translation control is an emerging research focus. Ectopically activated YAP is associated with the development of many human cancers. However, the mechanism whereby ALKBH5 regulates YAP expression and activity to inhibit NSCLC tumor growth and metastasis is not clear. Methods: Protein and transcript interactions were analyzed in normal lung cell and NSCLC cells. Gene expression was evaluated by qPCR and reporter assays. Protein levels were determined by immunochemical approaches. Nucleic acid interactions and status were analyzed by immunoprecipitation. Cell behavior was analyzed by standard biochemical tests. The m 6 A modification was analyzed by MeRIP. Results: Our results show that YAP expression is negatively correlated with ALKBH5 expression and plays an opposite role in the regulation of cellular proliferation, invasion, migration, and EMT of NSCLC cells. ALKBH5 reduced m 6 A modification of YAP. YTHDF3 combined YAP pre-mRNA depending on m 6 A modification. YTHDF1 and YTHDF2 competitively interacted with YTHDF3 in an m 6 A-independent manner to regulate YAP expression. YTHDF2 facilitated YAP mRNA decay via the AGO2 system, whereas YTHDF1 promoted YAP mRNA translation by interacting with eIF3a; both these activities are regulated by m 6 A modification. Furthermore, ALKBH5 decreased YAP activity by regulating miR-107/LATS2 axis in an HuR-dependent manner. Further, ALKBH5 inhibited tumor growth and metastasis in vivo by reducing the expression and activity of YAP. Conclusions: The presented findings suggest m 6 A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2-mediated YAP activity in NSCLC. Moreover, effective inhibition of m 6 A modification of ALKBH5 might constitute a potential treatment strategy for lung cancer.

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Section: Discussionmentioning

confidence: 99%

m6A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2–mediated YAP activity in NSCLC

et al. 2020

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“…1i) analysis. Publicly available datasets (http://www.kmplot.com/analysis/index.php?p=service&cancer=lung, 2015 version) [23,27,28] were screened to analyze prognostic correlations between YAP expression and the survival of patients with lung cancer. Kaplan–Meier analysis indicated that elevated YAP expression inversely correlated with overall survival (OS; p = 1.1e − 0.9 according to the log-rank test for significance; n = 1926) (Fig.…”

Section: Resultsmentioning

confidence: 99%

RETRACTED: The antineoplastic drug metformin downregulates YAP by interfering with IRF-1 binding to the YAP promoter in NSCLC

et al. 2018

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BackgroundActivation of the oncogene YAP has been shown to be related to lung cancer progression and associates with poor prognosis and metastasis. Metformin is a drug commonly used in the treatment of diabetes and with anticancer activity. However, the mechanism through which metformin inhibits tumorigenesis via YAP is poorly understood.MethodsThe mRNA and protein expressions were analyzed by RT-PCR and western blot. The cellular proliferation was detected by CCK8 and MTT. The cell migration and invasion growth were analyzed by wound healing assay and transwell assay. The activities of promoter were analyzed by luciferase reporter assay. Chromatin immunoprecipitation detected the combining ability of IRF-1 and 5′UTR-YAP.FindingsOur immunohistochemistry staining and RT-PCR assays showed that the expression of YAP was higher in lung carcinoma samples. Interestingly, metformin was able to downregulate YAP mRNA and protein expression in lung cancer cells. Mechanistically, we found that metformin depressed YAP promoter by competing with the binding of the transcription factor IRF-1 in lung cancer cells. Moreover, combination of metformin and verteporfin synergistically inhibits cell proliferation, promotes apoptosis and suppresses cell migration/invasion by downregulating YAP, therefore reduces the side effects caused by their single use and improve the quality of life for patients with lung cancer.Interpretationwe concluded that metformin depresses YAP promoter by interfering with the binding of the transcription factor IRF-1. Importantly, verteporfin sensitizes metformin-induced the depression of YAP and inhibition of cell growth and invasion in lung cancer cells.FundThis work was supported by National Natural Science Foundation of China (No.31801085), the Science and Technology Development Foundation of Yantai (2015ZH082), Natural Science Foundation of Shandong Province (ZR2018QH004, ZR2016HB55, ZR2017PH067 and ZR2017MH125), and Research Foundation of Binzhou Medical University (BY2015KYQD29 and BY2015KJ14).

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“…Our previous study demonstrated that NCTD suppressed YAP expression in NSCLC ( 26 ). Moreover, YAP activity has been reported to mediate drug resistance ( 27 , 28 ). To explore the effects of NCTD/DDP co-treatment on YAP, we used a luciferase reporter gene assay.…”

Section: Resultsmentioning

confidence: 99%

Norcantharidin reverses cisplatin resistance and inhibits the epithelial mesenchymal transition of human non‑small lung cancer cells by regulating the YAP pathway

Jin

Shao

et al. 2018

Oncol Rep

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Non-small cell lung cancer (NSCLC) accounts for >80% of all lung cancer cases, which are the leading cause of cancer-related mortality worldwide. The clinical efficacy of available therapies for NSCLC is often limited due to the development of resistance to anticancer drugs, particularly to cisplatin (DDP). Norcantharidin (NCTD) is a traditional Chinese medicine used in the treatment of many types of cancer, to which patients do not develop resistance. The aim of the present study was to examine the potential synergistic effects of NCTD and DPP on the viability of the the DDP-resistant NSCLC cell line, A549/DDP. We further explored the potential underlying mechanisms by examining the expression of the oncogene, Yes-associated protein 1 (YAP), whose activation was recently found to be associated with drug resistance. We further examined a series of human lung cancer cell lines and tissues from patients with lung cancer, which revealed that YAP activation contributed to lung cancer initiation, progression and metastasis, and was associated with a poor prognosis, and confering resistance against targeted therapies. Moreover, YAP expression was evaluated in the A549/DDP cells treated with NCTD, DDP, or both drugs. The combined treatment significantly sensitized the A549/DDP cells to DDP-induced growth inhibition by reducing YAP promoter activity (based on transcriptional expression) and the expression of its target genes, connective tissue growth factor (CTGF) and cysteine rich angiogenic inducer 61 (CYR61). Furthermore, compared to the individual treatments, combined treatment increased cell apoptosis and senescence, and decreased epithelial-to-mesenchymal transition and the cell migratory and invasive ability. On the whole, our data indicate that the application of NCTD with reverses DDP resistance and thus, this combined treatment may have promising prospects for use in improving the outcome of patients with NSCLC.

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Suppression of YAP by DDP disrupts colon tumor progression

Cited by 10 publications

References 35 publications

m6A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2–mediated YAP activity in NSCLC

m6A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2–mediated YAP activity in NSCLC

RETRACTED: The antineoplastic drug metformin downregulates YAP by interfering with IRF-1 binding to the YAP promoter in NSCLC

Norcantharidin reverses cisplatin resistance and inhibits the epithelial mesenchymal transition of human non‑small lung cancer cells by regulating the YAP pathway

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