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Cullin-9/p53 mediates HNRNPC degradation to inhibit erastin-induced ferroptosis and is blocked by MDM2 inhibition in colorectal cancer

Oncogene volume 41, pages 3210–3221 (2022)Cite this article

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Abstract

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.

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Fig. 1: CUL9 is clinically and functionally important for CRC.
Fig. 2: The biological function of CUL9 is stratified in CRC dependent on the TP53 gene status.
Fig. 3: Survivin is a substrate of the E3 ligase CUL9 in TP53mt CRC and exploration of the substrate of CUL9 in TP53wt CRC.
Fig. 4: CUL9 ubiquitinates HNRNPC by binding to p53 as a complex.
Fig. 5: The CUL9-HNRNPC-MATE1 axis influences erastin-induced ferroptosis in TP53wt CRC.
Fig. 6: Combined induction of Nutlin and Erastin enhances the antitumor effect in TP53wt CRC.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (Grant No. 81602040, 81903067, 82072678 and 81402341), Clinical science and technology innovation project of Shanghai (SHDC12016104), Shanghai Science and Technology Committee Project (17411951300, 18140903200 and 19511121300) and Youth fund of Zhongshan Hospital (2019ZSQN28). The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in the writing of the paper.

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  1. These authors contributed equally: Lv Yang, Tang WenTao, Zhang ZhiYuan, Lin Qi, Luo YuXiang.

Authors and Affiliations

  1. Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China

    Lv Yang, Tang WenTao, Zhang ZhiYuan, Lin Qi, Zheng Peng, Ji MeiLing, Feng QingYang, He GuoDong & Xu JianMin

  2. Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China

    Lv Yang, Tang WenTao, Zhang ZhiYuan, Lin Qi, Zheng Peng, Ji MeiLing, Feng QingYang, He GuoDong & Xu JianMin

  3. Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive Surgery, Shanghai, China

    Tang WenTao, Zhang ZhiYuan, Lin Qi, Zheng Peng, Ji MeiLing, Feng QingYang, He GuoDong & Xu JianMin

  4. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Luo YuXiang, Li Ke, Jia XiaoNa, Pang YuZhi & Wang YueXiang

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Contributions

Prof XJM and Prof WYX contributed to the design of the work and were the corresponding authors in this paper. Dr LY, TW, ZZ, LQ, ZP, and LYX performed the research, Dr LY, TW, LK, JX, PYZ, JML, FQY, and HGD analyzed and interpreted the patient data. Dr YL was a major contributor in writing the paper. Dr FQY and JML provided the research background and perspective views. Prof XJM and Prof WYX were the corresponding authors and approved the final version of this paper to be published.

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Correspondence to Wang YueXiang or Xu JianMin.

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Written informed consent was obtained by all the patients. The study protocol followed the ethical guidelines of the Declaration of Helsinki and was approved by the Ethical Committee of Zhongshan Hospital of Fudan University. The ethics approval ID was B2017-166R.

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Yang, L., WenTao, T., ZhiYuan, Z. et al. Cullin-9/p53 mediates HNRNPC degradation to inhibit erastin-induced ferroptosis and is blocked by MDM2 inhibition in colorectal cancer. Oncogene 41, 3210–3221 (2022). https://doi.org/10.1038/s41388-022-02284-z

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