IRF1 suppresses colon cancer proliferation by reducing SPI1-mediated transcriptional activation of GPX4 and promoting ferroptosis.

Abstract

IRF1 is a tumor suppressor gene in colon cancer. This study aimed to explore the potential regulation of IRF1 on the ferroptosis of colon cancer and the mechanisms underlying its regulation of GPX4 transcription. IRF1 interacting transcription factors regulating GPX4 transcription were predicted and validated. The role of the IRF1/SPI1-GPX4 axis on the ferroptosis of colon cancer cells was explored. Results showed that IRF1 overexpression reduced GPX4 transcription, increased reactive oxygen species (ROS) and lipid ROS accumulation, and enhanced erastin-induced colon cancer cell growth in vitro and in vivo. SPI1 could directly bind to the GPX4 promoter (-414 to -409) and activate its transcription. IRF1 could bind to SPI1 and suppress its transcriptional activating effects on GPX4 expression. SPI1 overexpression reduced ROS and lipid ROS accumulation and increased colon cancer cell viability and colony formation upon erastin induction. These trends were reversed by IRF1 overexpression. In conclusion, this study revealed a novel oncogenic mechanism of SPI1 by reducing erastin-induced ferroptosis in colon cancer. IRF1 interacts with SPI1 and suppresses its transcriptional activating effect on GPX4 expression. Through this mechanism, IRF1 can enhance erastin-induced ferroptosis of colon cancer. The IRF1/SPI1-GPX4 axis might play a crucial role in modulating ferroptosis in colon cancer and might serve as a potential therapeutic target in the future.

• Authors: Yilin Chen, Beian Lin, Shiyu Yang, Jingshan Huang
• Journal: Experimental cell research (Exp Cell Res) Vol. 431 Issue 1 Pg. 113733 (10 01 2023) ISSN: 1090-2422 [Electronic] United States
• PMID: 37517591 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• Reactive Oxygen Species
• Lipids
• IRF1 protein, human
• Interferon Regulatory Factor-1

Topics

• Humans
• Ferroptosis (genetics)
• Reactive Oxygen Species
• Transcriptional Activation (genetics)
• Colonic Neoplasms (genetics)
• Cell Proliferation (genetics)
• Lipids
• Interferon Regulatory Factor-1 (genetics)