MCM8 Promotes NSCLC Progression by Competitively Inhibiting HRD1-Mediated CDC42 Ubiquitination and Degradation

Colon cancer ranks among the top three in both the incidence and mortality rates of malignant tumors worldwide. Moreover, radical surgery is difficult for patients with advanced colon cancer, and chemotherapy drugs are prone to drug resistance. The five-year survival rate is only 13.1%. Therefore, an in-depth analysis of the occurrence, development and drug resistance mechanism of colon cancer is of great clinical significance for optimizing the treatment plan of patients and improving prognosis. As one of the homologous recombination repair proteins, micrormosomal maintenance protein 8 (MCM8) plays an important role in the normal physiological process of cells. In recent years, the research on its role in tumorigenesis and development has gradually deepened, but the role of MCM8 in the malignant progression of colon cancer still remains to be explored. MCM8 is abnormally highly expressed in colon cancer cells and tissues, and is positively correlated with the pathological stage progression and poor prognosis of patients. Our study indicated that MCM8 promotes the transition of the cell cycle from the G1 phase to the S phase. Moreover, our study showed that MCM8 interacted with Cdc42 and promoted its protein stability by competitively inhibiting the ubiquitination modification of Cdc42's E3 ubiquitin ligase HRD1. The rescue experiment showed that MCM8 promoted the proliferation, cell cycle progression, invasion, tumor-forming ability in vivo and resistance to 5-FU of colon cancer cells through Cdc42, while inhibiting cell apoptosis. Collectively, MCM8 is abnormally highly expressed in colon cancer and stabilizes Cdc42 protein by competitively inhibiting HRD1, thereby promoting the occurrence and development of colon cancer and the formation of 5-FU resistance.