泛素蛋白酶体系统（UPS）的功能障碍涉及包括结直肠癌（CRC）在内的多种恶性肿瘤的发病机制。泛素结构域包含 1 (UBTD1) 是一种泛素样蛋白，在某些癌症类型中调节 UPS 介导的蛋白降解和肿瘤进展。然而，UBTD1的生物学功能和机制尚未得到很好的阐明，其在结直肠癌中的作用尚未被探索。在我们的研究中，我们分析了CRC患者的临床信息和UBTD1表达数据，发现癌组织中UBTD1的表达显着高于癌旁正常组织。较高的 UBTD1 表达与较差的生存率和更多的淋巴结转移显着相关。 UBTD1 的过表达可以促进 CRC 细胞的增殖和迁移，而敲低则可以抑制 CRC 细胞的增殖和迁移。 RNA-seq和蛋白质组学表明c-Myc是UBTD1的重要下游靶标。代谢组学显示，UBTD1 过表达细胞中糖酵解途径的产物显着增加。在体外，我们验证了UBTD1上调c-Myc蛋白并通过调节c-Myc促进CRC细胞增殖和迁移。 UBTD1 过表达后乳酸生成和葡萄糖摄取增加证明了 UBTD1 促进了 CRC 细胞的糖酵解。从机制上讲，UBTD1通过与E3连接酶β-转导蛋白重复序列​​蛋白（β-TrCP）结合，延长c-Myc蛋白的半衰期，从而上调糖酵解限速酶己糖激酶II（HK2）的表达，并增强糖酵解并促进CRC进展。总之，我们的研究表明，UBTD1 通过 β-TrCP/c-Myc/HK2 途径上调糖酵解来促进 CRC 进展，表明其作为 CRC 预后生物标志物和治疗靶点的潜力。© 2024。作者。

Dysfunction of the ubiquitin-proteasome system (UPS) is involved in the pathogenesis of various malignancies including colorectal cancer (CRC). Ubiquitin domain containing 1 (UBTD1), a ubiquitin-like protein, regulates UPS-mediated protein degradation and tumor progression in some cancer types. However, the biological function and mechanism of UBTD1 are far from being well elucidated, and its role in CRC has not been explored yet. In our study, we analyzed CRC patients' clinical information and UBTD1 expression data, and found that the expression of UBTD1 in cancer tissue was significantly higher than that in adjacent normal tissue. Higher UBTD1 expression was significantly associated with poorer survival and more lymph node metastasis. Overexpression of UBTD1 could facilitate, while knockdown could inhibit CRC cell proliferation and migration, respectively. RNA-seq and proteomics indicated that c-Myc is an important downstream target of UBTD1. Metabolomics showed the products of the glycolysis pathway were significantly increased in UBTD1 overexpression cells. In vitro, we verified UBTD1 upregulating c-Myc protein and promoting CRC cell proliferation and migration via regulating c-Myc. UBTD1 promoted CRC cells' glycolysis, evidenced by the increased lactate production and glucose uptake following UBTD1 overexpression. Mechanistically, UBTD1 prolonged the half-life of the c-Myc protein by binding to E3 ligase β-transducin repeat-containing protein (β-TrCP), thereby upregulated the expression of glycolysis rate-limiting enzyme hexokinase II (HK2), and enhanced glycolysis and promoted CRC progression. In conclusion, our study revealed that UBTD1 promotes CRC progression by upregulating glycolysis via the β-TrCP/c-Myc/HK2 pathway, suggesting its potential as a prognostic biomarker and therapeutic target in CRC.© 2024. The Author(s).