CUL4B-DDB1-COP1-mediated UTX downregulation promotes colorectal cancer progression

• DOI: 10.1186/s40164-023-00440-z
• Publication Date: 2023-09-07T04:02:03Z
• Authors: Dakui Luo; Min Chen; Qingguo Li; Kangjunjie Wang; Kaihua Wang; Junqiang Li; Guoxiang Fu; Zezhi Shan; Qi Liu; Yufei Yang; Lei Liang; Yanlei Ma; Yi Qin; Jun Qin; Daming Gao; Xinxiang Li
• Keywords: Ubiquitylation; UTX; Research; COP1; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Diseases of the blood and blood-forming organs; RC633-647.5; Colorectal cancer; RC254-282; 3. Good health

UTX (encoded by KDM6A), a histone demethylase for H3K27me2/3, is frequently mutated in human cancers. However, its functional and regulatory mechanisms colorectal cancer (CRC) remain unclear.Immunohistochemistry staining was used to investigate the clinical relevance of CRC. Additionally, we generated spontaneous mouse CRC model with conditional Utx knockout explore role tumorigenesis. Post-translational regulation determined co-immunoprecipitation immunoblot analyses.Herein, identify that downregulation UTX, mediated Cullin 4B-DNA Damage Binding Protein-1-Constitutive Photomorphogenesis Protein 1 (CUL4B-DDB1-COP1) complex, promotes progression. deletion intestinal epithelial cells enhanced susceptibility tumorigenesis AOM/DSS-induced model. this effect primarily alleviated GSK126, an inhibitor methyltransferase EZH2. Mechanistically, EMP1 AUTS2 are identified as putative target genes mediating functions limiting Notably, CUL4B-DDB1-COP1 complex E3 ligase responsible targeting degradation cells. Thus, Cop1 deficiency tissue results accumulation restricts Furthermore, patient cohort analysis reveals expression negatively correlated stage, favorable disease outcomes, COP1 expression.In current study, tumor suppressor function provide molecular basis rationale EZH2 UTX-deficient