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The antitumor peptide M1-20 induced the degradation of CDK1 through CUL4-DDB1-DCAF1-involved ubiquitination

Cancer Gene Therapy volume 32, pages 61–70 (2025)Cite this article

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Abstract

CDK1 is an oncogenic serine/threonine kinase known to play an important role in the regulation of the cell cycle. FOXM1, as one of the CDK1 substrates, requires binding of CDK1/CCNB1 complex for phosphorylation-dependent recruitment of p300/CBP coactivators to mediate transcriptional activity. Previous studies from our laboratory found that a novel peptide (M1-20) derived from the C-terminus of FOXM1 exhibited potent inhibitory effects for cancer cells. Based on these proofs and to explore the inhibitory mechanism of M1-20, we designed experiments and found that CDK1 served as an important target of M1-20. M1-20 enhanced the ubiquitination and degradation of CDK1 by CUL4-DDB1-DCAF1 complexes through the proteasome pathway. M1-20 could also affect the formation of CDK1/CCNB1 complexes. In addition, compared to RO3306, a CDK1 inhibitor, M1-20 exhibited excellent inhibitory effects in FVB/N MMTV-PyVT murine model of spontaneous breast cancer. These results suggested that M1-20 was a potential CDK1 inhibitor for the treatment of cancer.

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Fig. 1: M1-20 bound to CDK1.
Fig. 2: M1-20 mediated the degradation of CDK1 by the ubiquitin-proteasome pathway.
Fig. 3: Identification of CDK1 as a new substrate of DCAF1.
Fig. 4: M1-20 ubiquitinated CDK1 by CUL4-DDB1-DCAF1 complexes.
Fig. 5: M1-20 abolished the interaction between CDK1 and CCNB1.
Fig. 6: M1-20 inhibited the initiation and progression of spontaneous breast cancer.

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Data availability

All data generated or analyzed during this study are included in this article and its Supplementary Information files. Additional data are available from the corresponding author on reasonable request.

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Funding

This study was supported by grants from the National Natural Science Foundation of China (No. 81773169, No. 81472718), Hunan Key R&D Project (2023SK2040), China Changsha Development and Reform Commission “Mass entrepreneurship and innovation program” (2018-68) and “Innovation platform construction program” (2018-216), Hunan Natural Science Foundation (812202201381).

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Authors and Affiliations

  1. State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan Engineering Research Center for Anticancer Targeted Protein Pharmaceuticals, Hunan University, Changsha, Hunan, China

    Huitong Bu, Chaozhu Pei, Min Ouyang, Yan Chen, Li Yu, Xiaoqin Huang & Yongjun Tan

  2. Institutes of Health Central Plains, Xinxiang Medical University, Xinxiang, Henan, China

    Huitong Bu

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  1. Huitong Bu
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Contributions

YT designed the study. HB performed the most experiments and analyzed the data. CP and MO contributed to data acquisition or analysis. YT, LY, and XH provided support with experiments. YT and HB wrote and edited the manuscript. YT, LY, XH, and YC supervised the project, and YT performed project administration and funding acquisition.

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Correspondence to Yongjun Tan.

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Competing interests

A patent on M1-20 and its derivatives has been granted in China (ZL202011200439.0). Y. T. and H. B. are co-inventors of this patent. This does not alter the authors′ adherence to the policies on sharing data and materials.

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All animal care and experiments were performed in accordance with guidelines, approved by the Laboratory Animal Center of Hunan, China (Protocol No. SYXK [Xiang] 2018-0006).

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Bu, H., Pei, C., Ouyang, M. et al. The antitumor peptide M1-20 induced the degradation of CDK1 through CUL4-DDB1-DCAF1-involved ubiquitination. Cancer Gene Ther 32, 61–70 (2025). https://doi.org/10.1038/s41417-024-00855-8

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