Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
Oncogene. 2022 Jun;41(23):3210-3221. doi: 10.1038/s41388-022-02284-z. Epub 2022 May 3.
Colorectal cancer (CRC) is the leading cause of cancer associated death worldwide. Ferroptosis is a newly defined form of regulated cell death characterized by the accumulation of lipid hydroperoxides and exerts an increased attention for cancer treatment. However, little is known about ferroptosis in CRC. In this study, through whole genome sequencing and external differential differentiated expression analysis, we identify CUL9 as a novel important modulator for ferroptosis in CRC. Here we demonstrated that CUL9 can binds p53 to ubiquitylate heterogeneous nuclear ribonucleoprotein C for degradation. Overexpression of CUL9 increases resistance to erastin-induced ferroptosis. Then, we discovered this resistance was mediated by CUL9-HNRNPC-MATE1 negative loop, which can provide us with a novel target to overcome drug resistance to ferroptosis activators. Finally, we found that targeting MDM2 was developed as an effective strategy to destroy precious drug-resistant CRC cells.
结直肠癌（CRC）是全球癌症相关死亡的主要原因。铁死亡是一种新定义的受调控的细胞死亡形式，其特征是脂质氢过氧化物的积累，并引起了人们对癌症治疗的关注。然而，CRC 中的铁死亡知之甚少。在这项研究中，通过全基因组测序和外部差异表达分析，我们确定 CUL9 是 CRC 中铁死亡的一个新的重要调节剂。在这里，我们证明 CUL9 可以与 p53 结合，使异质核核糖核蛋白 C 泛素化降解。CUL9 的过表达增加了对 erastin 诱导的铁死亡的抗性。然后，我们发现这种抗性是由 CUL9-HNRNPC-MATE1 负反馈回路介导的，这为克服铁死亡激活剂的耐药性提供了一个新的靶点。最后，我们发现靶向 MDM2 是破坏珍贵的耐药 CRC 细胞的有效策略。
