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FOXA2 Suppression by TRIM36 Exerts Anti-Tumor Role in Colorectal Cancer Via Inducing NRF2/GPX4-Regulated Ferroptosis
Xin Liu1, Chunli Yan2, Chunxiao Chang3
1Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, China.
Abstract:
The forkhead box transcription factor A2 (FOXA2) is a transcription factor and plays a key role in embryonic development, metabolism homeostasis and tumor cell proliferation; however, its regulatory potential in CRC is not fully understood. Here, it is found that FOXA2 expression is markedly up-regulated in tumor samples of CRC patients as compared with the normal tissues, which is closely associated with the worse survival in patients with CRC. Notably, a positive correlation between FOXA2 and nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) gene expression is observed in CRC patients. Mechanistically, FOXA2 depletion weakens the activation of Nrf2 pathway and decreases GPX4 level in CRC cells, thereby leading to ferroptosis, which is further supported by bioinformatic analysis. More intriguingly, the E3 ubiquitin ligase tripartite motif containing 36 (TRIM36) is identified as a key suppressor of FOXA2, and it is observed that TRIM36 can directly interact with FOXA2 and induce its K48-linked polyubiquitination, resulting in FOXA2 protein degradation in vitro. Taken together, all the studies demonstrate that FOXA2 mediated by TRIM36 promotes CRC progression by inhibiting the Nrf2/GPX4 ferroptosis signaling pathway, thus providing a new therapeutic target for CRC treatment.
Insights
Forkhead box transcription factor A2 (FOXA2) promotes colorectal cancer (CRC) progression by inhibiting ferroptosis. Tripartite motif containing 36 (TRIM36) suppresses FOXA2, offering a potential therapeutic target for CRC.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Signaling
Background:
- The role of forkhead box transcription factor A2 (FOXA2) in colorectal cancer (CRC) remains unclear.
- FOXA2 is implicated in embryonic development, metabolic homeostasis, and tumor cell proliferation.
Purpose of the Study:
- To investigate the regulatory role and mechanism of FOXA2 in CRC progression.
- To identify potential therapeutic targets for CRC treatment.
Main Methods:
- Analysis of FOXA2 expression in CRC tumor samples and normal tissues.
- Correlation analysis between FOXA2, nuclear factor erythroid 2-related factor 2 (Nrf2), and glutathione peroxidase 4 (GPX4) gene expression.
- Investigation of FOXA2 depletion effects on Nrf2 pathway and GPX4 levels in CRC cells.
- Identification and characterization of tripartite motif containing 36 (TRIM36) as a FOXA2 regulator.
- Bioinformatic analysis and in vitro ubiquitination assays.
Main Results:
- FOXA2 expression is significantly upregulated in CRC tissues and associated with poorer patient survival.
- A positive correlation exists between FOXA2 and Nrf2/GPX4 expression in CRC.
- FOXA2 depletion induces ferroptosis in CRC cells by weakening Nrf2 pathway activation and decreasing GPX4 levels.
- TRIM36 directly interacts with FOXA2, promoting its degradation via K48-linked polyubiquitination.
- TRIM36 acts as a suppressor of FOXA2.
Conclusions:
- FOXA2 promotes CRC progression by inhibiting the Nrf2/GPX4-mediated ferroptosis pathway.
- TRIM36-mediated degradation of FOXA2 represents a novel mechanism regulating CRC.
- Targeting FOXA2 or its regulatory pathway presents a potential therapeutic strategy for CRC.
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