<br>TRIM36 抑制 FOXA2 通过诱导 NRF2/GPX4 调节的铁死亡在结直肠癌中发挥抗肿瘤作用,Advanced Science

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TRIM36 抑制 FOXA2 通过诱导 NRF2/GPX4 调节的铁死亡在结直肠癌中发挥抗肿瘤作用
Advanced Science ( IF 14.3 ) Pub Date : 2023-10-24 , DOI: 10.1002/advs.202304521
Xin Liu ₁ , Chunli Yan ₂ , Chunxiao Chang ₃ , Fansong Meng ₄ , Wenjie Shen ₅ , Song Wang ₄ , Yi Zhang ₁

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叉头盒转录因子A2（FOXA2）是一种转录因子，在胚胎发育、代谢稳态和肿瘤细胞增殖中发挥关键作用；然而，其在 CRC 中的监管潜力尚未得到充分了解。本研究发现，与正常组织相比，CRC患者的肿瘤样本中FOXA2表达显着上调，这与CRC患者较差的生存率密切相关。值得注意的是，在 CRC 患者中观察到 FOXA2 与核因子红细胞 2 相关因子 2 (Nrf2)/谷胱甘肽过氧化物酶 4 (GPX4) 基因表达呈正相关。从机制上讲，FOXA2耗竭削弱了Nrf2通路的激活并降低了CRC细胞中的GPX4水平，从而导致铁死亡，生物信息学分析进一步支持了这一点。更有趣的是，含有36的E3泛素连接酶三联基序（TRIM36）被鉴定为FOXA2的关键抑制因子，并且观察到TRIM36可以直接与FOXA2相互作用并诱导其K48连接的多泛素化，导致FOXA2蛋白在体外降解。综上所述，所有研究均表明TRIM36介导的FOXA2通过抑制Nrf2/GPX4铁死亡信号通路促进CRC进展，从而为CRC治疗提供了新的治疗靶点。

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

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.

更新日期：2023-10-24

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