Title:Gliotoxin Induced Ferroptosis by Downregulating SUV39H1 Expression in
Esophageal Cancer Cells
Volume: 18
Issue: 3
Author(s): Shengqiang Zhang, Jida Guo, Hongyan Zhang, Lu Tong and Linyou Zhang*
Affiliation:
- Department of Thoracic Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang,
P. R. China
Keywords:
Gliotoxin, natural compounds, esophageal squamous cell carcinoma, ferroptosis, SUV39H1, cancer therapy.
Abstract:
Background: Gliotoxin, a secondary metabolite isolated from marine-derived Aspergillus
fumigatus, has demonstrated anti-tumor properties in several cancers. Ferroptosis, a recently
discovered type of programmed cell death that depends on the accumulation of iron and lipid peroxides,
participates in the occurrence and development of various diseases, including cancer. A
recent patent, US20200383943, has suggested that the promotion of ferroptosis is a method of
cancer treatment. Therefore, the development of drugs that induce ferroptosis in cancer cells
would constitute a novel therapeutic approach.
Objective: Gliotoxin is a natural compound which has exhibited anti-tumor properties in multiple
cancers, however, studies of the effect of gliotoxin on esophageal cancer are lacking. Although
cancer treatment has shown great progress, including traditional surgery, chemotherapy, radiotherapy,
and immunotherapy, the prognosis of esophageal cancer is still poor. Therefore, the development
of new treatment approaches for esophageal cancer is necessary.
Methods: The effects of gliotoxin on esophageal cancer cells were determined by functional assays,
such as CCK-8, wound healing and transwell assays. We used online tools to predict the target
genes of gliotoxin, followed by further verification using Western blotting assays. To assess
the role of gliotxin in inducing ferroptosis in esophageal cancer, we detected characteristics associated
with ferroptosis including ROS, MDA, GSH and Fe2+.
Results: Using online tools SEA and SwissTargetPrediction, we predicted that SUV39H1 was the
gliotoxin target gene. Furthermore, in esophageal cancer tissues, SUV39H1 was expressed at
higher levels than in normal tissues, while in patients with Esophageal Squamous Cell Carcinoma
(ESCC), high expression levels of SUV39H1 indicated a poor prognosis. In vitro, we observed
that gliotoxin increased ESCC cell death and inhibited cell migration. We treated ESCC cells with
pan-caspase inhibitor Z-VAD-FMK or ferroptosis inhibitors, including Fer-1 and DFO. Our results
showed that Fer-1 and DFO reduced the toxic effects of gliotoxin, while Z-VAD-FMK did
not. Furthermore, gliotoxin treatment reduced tumor weight and volume in the xenograft tumor
mouse model.
Conclusion: In summary, our findings indicate that gliotoxin downregulated SUV39H1 expression
in ESCC cells and induced ferroptosis, suggesting a novel natural therapy for ESSC.