UTX（由KDM6A编码）是H3K27me2/3的组蛋白去甲基化酶，在人类癌症中经常发生突变。然而，其在结直肠癌（CRC）中的功能和调控机制尚不清楚。本研究采用免疫组织化学染色方法，研究了UTX在CRC中的临床相关性。此外，我们通过条件性Utx基因敲除建立了一种自发性小鼠CRC模型，以探索UTX在结直肠肿瘤发生中的作用。通过共免疫共沉淀和免疫印迹分析确定了UTX的翻译后修饰调控。在本研究中，我们发现Cullin 4B-DNA损伤结合蛋白1-持续性光态调控蛋白1（CUL4B-DDB1-COP1）复合物介导的UTX下调促进了CRC的进展。在AOM/DSS诱导的自发性小鼠CRC模型中，肠上皮细胞中的Utx删除增加了易感性。然而，组蛋白甲基转移酶EZH2抑制剂GSK126主要缓解了这种影响。在机制上，我们鉴定了EMP1和AUTS2作为可能的UTX靶基因，介导了UTX在限制肠道肿瘤发生中的功能。值得注意的是，我们发现CUL4B-DDB1-COP1复合物是CRC细胞中靶向UTX降解的功能E3连接酶。因此，小鼠肠组织中Cop1的缺陷导致UTX积累并限制肿瘤发生。此外，患者队列分析显示UTX表达与临床分期、有利的疾病结局和COP1表达呈负相关。本研究的结果为CRC中UTX的肿瘤抑制功能和调控提供了分子基础和靶向UTX缺陷的EZH2的合理依据。 © 2023. YUMED Inc. and BioMed Central Ltd.

UTX (encoded by KDM6A), a histone demethylase for H3K27me2/3, is frequently mutated in human cancers. However, its functional and regulatory mechanisms in colorectal cancer (CRC) remain unclear.Immunohistochemistry staining was used to investigate the clinical relevance of UTX in CRC. Additionally, we generated a spontaneous mouse CRC model with conditional Utx knockout to explore the role of UTX in the colorectal tumorigenesis. Post-translational regulation of UTX was determined by co-immunoprecipitation and immunoblot analyses.Herein, we identify that downregulation of UTX, mediated by the Cullin 4B-DNA Damage Binding Protein-1-Constitutive Photomorphogenesis Protein 1 (CUL4B-DDB1-COP1) complex, promotes CRC progression. Utx deletion in intestinal epithelial cells enhanced the susceptibility to tumorigenesis in AOM/DSS-induced spontaneous mouse CRC model. However, this effect is primarily alleviated by GSK126, an inhibitor of histone methyltransferase EZH2. Mechanistically, EMP1 and AUTS2 are identified as putative UTX target genes mediating UTX functions in limiting intestinal tumorigenesis. Notably, the CUL4B-DDB1-COP1 complex is identified as the functional E3 ligase responsible for targeting UTX for degradation in CRC cells. Thus, Cop1 deficiency in mouse intestinal tissue results in UTX accumulation and restricts tumorigenesis. Furthermore, patient cohort analysis reveals that UTX expression is negatively correlated with clinical stage, favorable disease outcomes, and COP1 expression.In the current study, the tumor suppressor function and regulation of UTX in CRC provide a molecular basis and the rationale to target EZH2 in UTX-deficient CRC.© 2023. YUMED Inc. and BioMed Central Ltd.