Role of inhibitor of growth 4 in the suppression of human melanoma cells through the Fas/FasL-mediated apoptosis pathway

Int J Mol Med. 2018 Feb;41(2):1055-1061. doi: 10.3892/ijmm.2017.3274. Epub 2017 Nov 20.


Melanoma, the most aggressive form of skin cancer, is notoriously resistant to all current available therapies. Inhibitor of growth 4 (ING4), a novel member of the ING family of proteins, has previously been shown to play a critical role in the development of multiple tumors by regulating apoptosis, proliferation, cell cycle progress, migration and invasion. However, the functional role of ING4 in human melanoma remains unclear. To fully understand its potential role in human melanoma, in the present study, lentivirus (LV)‑ING4 and LV‑ING4‑short hairpin RNA were constructed and transfected into human melanoma A375 cells. First, the effect of overexpressing or downregulating ING4 on the apoptosis of the transfected melanoma cells and cluster of differentiation (CD)3+ T cells was investigated. In the present study, we found that the late apoptotic cells, and not the early apoptotic cells, were more in LV-ING4 group compared with LV-control, and both the early and late apoptosis of CD3+ T cells was significantly observed in A375 cells transfected with LV-ING4 compared with LV-control. Importantly, it was determined whether the overexpression of ING4 significantly induce apoptotic cell death via Fas/FasL (Fas death receptor/FasL) pathway activation and downregulation of poly(ADP‑ribose) polymerase, caspase‑3 and caspase‑8 in the melanoma cells and CD3+ T cells. These results demonstrated that overexpression of ING4 can induce the apoptosis of melanoma cells and CD3+ T cells through signaling pathways such as the Fas/FasL pathway, and that ING4 gene therapy for melanoma treatment is a novel approach.

MeSH terms

  • Apoptosis / genetics
  • Caspase 8 / genetics
  • Cell Cycle Proteins / administration & dosage
  • Cell Cycle Proteins / genetics*
  • Cell Line, Tumor
  • Cell Proliferation
  • Fas Ligand Protein / genetics*
  • Gene Expression Regulation, Neoplastic
  • Genetic Therapy / methods
  • Genetic Vectors / administration & dosage
  • Homeodomain Proteins / administration & dosage
  • Homeodomain Proteins / genetics*
  • Humans
  • Lentivirus / genetics
  • Melanoma / genetics*
  • Melanoma / pathology
  • Transfection
  • Tumor Suppressor Proteins / administration & dosage
  • Tumor Suppressor Proteins / genetics*
  • fas Receptor / genetics*


  • Cell Cycle Proteins
  • FASLG protein, human
  • Fas Ligand Protein
  • Homeodomain Proteins
  • ING4 protein, human
  • Tumor Suppressor Proteins
  • fas Receptor
  • Caspase 8