IRF7 inhibits the Warburg effect via transcriptional suppression of PKM2 in osteosarcoma
Zhikun Li1, Mei Geng2, Xiaojian Ye1
1Department of Orthopedics, Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200336, China.
Abstract:
Osteosarcoma (OS) is a malignant bone tumor among adolescents and young adults. IRF7 belongs to the transcription factor family of interferon regulatory factors (IRFs) and has previously been described to function as a tumor suppressor in multiple cancer types. However, the biological functions and cellular mechanism of IRF7 in OS remain elusive. In this study, by quantitative real-time PCR (qRT-PCR) and western blotting, we found that IRF7 was downregulated in OS, and the higher expression of IRF7 was correlated with a better survival prognosis. Moreover, loss-of-function and gain-of-function studies have proved the critical functions of IRF7 in suppressing aerobic glycolysis of osteosarcoma cells as evidenced by glucose uptake, lactate production, extracellular acidification rate, and oxygen consumption rate. Mechanistically, IRF7 inhibited the expression of key glycolytic gene PKM2 via direct transcriptional regulation. Moreover, the in vitro and in vivo tumor-suppressive roles of IRF7 were uncovered in OS and these effects were largely glycolysis-dependent. Therefore, our study unveils a previous unprecedented role of IRF7 in glucose metabolism reprogram and suggests that IRF7 might serve as a potential therapeutic target for patients with OS.
Insights
Interferon regulatory factor 7 (IRF7) suppresses aerobic glycolysis in osteosarcoma (OS) by regulating the PKM2 gene. This finding reveals IRF7 as a potential therapeutic target for OS patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Osteosarcoma (OS) is a prevalent bone cancer in adolescents and young adults.
- Interferon regulatory factor 7 (IRF7) is known to act as a tumor suppressor in various cancers, but its role in OS is unclear.
Purpose of the Study:
- To investigate the biological functions and cellular mechanisms of IRF7 in osteosarcoma.
- To explore the potential of IRF7 as a therapeutic target for OS.
Main Methods:
- Quantitative real-time PCR (qRT-PCR) and Western blotting were used to assess IRF7 expression.
- Loss-of-function and gain-of-function studies evaluated IRF7's impact on glycolysis.
- Mechanistic studies examined IRF7's regulation of the PKM2 gene.
Main Results:
- IRF7 expression was found to be downregulated in OS tissues, with higher IRF7 levels correlating with better patient survival.
- IRF7 significantly suppressed aerobic glycolysis in OS cells, as indicated by reduced glucose uptake and lactate production.
- IRF7 directly inhibited PKM2 gene expression, a key regulator of glycolysis.
Conclusions:
- IRF7 plays a crucial role in suppressing osteosarcoma cell glycolysis through direct transcriptional regulation of PKM2.
- IRF7 exhibits tumor-suppressive effects in OS, both in vitro and in vivo, largely dependent on its metabolic regulation.
- IRF7 represents a promising therapeutic target for reprogramming glucose metabolism in osteosarcoma.
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