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

EBioMedicine. 2018 Nov:37:188-204. doi: 10.1016/j.ebiom.2018.10.044. Epub 2018 Oct 30.

Abstract

Background: Activation 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.

Methods: The 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.

Findings: Our 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.

Interpretation: we 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. FUND: This 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).

Keywords: EMT; IRF-1; Lung cancer; Metformin; Verteporfin; YAP.

Publication types

  • Retracted Publication

MeSH terms

  • A549 Cells
  • Adaptor Proteins, Signal Transducing / biosynthesis*
  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Down-Regulation / drug effects*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / metabolism*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Metformin / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phosphoproteins / biosynthesis*
  • Phosphoproteins / genetics
  • Promoter Regions, Genetic*
  • Transcription Factors
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • Phosphoproteins
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Metformin