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

Abstract

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).

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

“…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.…”

Metformin-repressed miR-381-YAP-snail axis activity disrupts NSCLC growth and metastasis

“…*P < 0.05 or **P < 0.01 indicates a significant difference between the indicated groups (two-tailed, unpaired Student's t-test or one-way analysis of variance) tumor prevention and, therefore, the prolonged and increased use of metformin can significantly reduce the risk of malignant tumors. Moreover, our previously published research showed that metformin downregulates YAP by interfering with IRF-1 binding to the YAP promoter, and inhibits cancer growth and metastasis in NSCLC [4]. Furthermore, recent studies have shown that metformin inhibits human cancer growth and metastasis by regulating miRNAs [9,10].…”

“…Metformin decreases cell growth, migration, invasion, and EMT by regulating miR-381/YAP activity Recent studies indicate that metformin decreases cell growth and metastasis by regulating miRNAs in human cancers [9,10]. Additionally, our previous research showed that the antineoplastic drug metformin downregulates YAP in NSCLC by interfering with IRF-1 binding to the YAP promoter [4]. However, the molecular mechanism through which metformin decreases YAP activity by regulating miR-381 was not clear.…”

“…Additionally, LATS1/2 can be activated by an AMPK-dependent pathway to suppress YAP activity by phosphorylating YAP at S127, leading to the retention of YAP in the cytoplasm and the promotion of its degradation [3]. In addition, our previous study indicated that metformin downregulates YAP by interfering with interferon regulatory factor 1 (IRF-1) binding to the YAP promoter, inhibiting NSCLC growth and metastasis [4]. Moreover, several studies showed that the use of metformin was associated with a lower risk of lung cancer among patients with diabetes and improved survival of NSCLC patients with diabetes [5][6][7].…”

The Role of Photoactivated and Non-Photoactivated Verteporfin on Tumor

“…The insulin sensitizer metformin competitively binds to the transcription factor IRF-1 to inhibit the expression of YAP in A549 lung cancer cells. VP augmented the effect of metformin on YAP in lung cancer cells, and reduced the number of tumors in xenograft-bearing mice ( Jin et al, 2018 ). In addition, the transcriptome of VP-treated endometrial cancer cells showed differential expression of 549 genes involved in TGFβ1 regulation, lipoprotein metabolism, cell adhesion, endoderm cell differentiation, and integrin-mediated signaling pathways relative to that in the control cells.…”