The antitumor peptide M1-20 induced the degradation of CDK1 through CUL4-DDB1-DCAF1-involved ubiquitination
- Cancer Gene Ther. 2025 Jan;32(1):61-70. doi: 10.1038/s41417-024-00855-8.
- 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.
- 2. Institutes of Health Central Plains, Xinxiang Medical University, Xinxiang, Henan, China.
- 3. 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. [email protected].
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.