FOXA2 Suppression by TRIM36 Exerts Anti‐Tumor Role in Colorectal Cancer Via Inducing NRF2/GPX4‐Regulated Ferroptosis

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.

The application of graphene oxide and ferroptosis in the diagnosis and treatment of colorectal cancer: a narrative review

“…Ferroptosis is associated with multiple signaling pathways in the treatment of CRC. For example, interferon gamma (IFNγ), in conjunction with cold plasma, triggers ferroptosis in CRC cells through the IFNγ/IFNR2/APC/TCF4/GPX4 axis ( 75 ), CAPG interference induces apoptosis and ferroptosis in colon cancer cells through the P53 pathway ( 76 ), while TRIM36 inhibition of FOXA2 plays an antitumor role in CRC by inducing NRF2/GPX4-regulated ferroptosis ( 77 ). Additionally, certain natural substances and drugs can induce or inhibit ferroptosis, thereby affecting the growth of CRC cells, such as osthole, ginsenosides, puerarin, curcumin, and andrographolide ( 78 - 82 ).…”

Inhibition of the p62-Nrf2-GPX4 Pathway Confers Sensitivity to Butachlor-Induced Splenic Macrophage Ferroptosis

“…Nrf2 has also received attention as a redox-sensitive transcription factor relevant to iron metabolism . It has been indicated that Nrf2 signaling pathway can protect cells from ferroptosis in a number of chronic diseases through increased expression of solute carrier family 7 member 11 (SLC7A11) and GPX4 . P62 is a multifunctional protein that regulates various signaling pathways, including autophagy, oxidative stress, and DNA damage .…”