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Abstract：
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.
摘要：
泛素-蛋白酶体系统（UPS）的功能障碍与包括结直肠癌（CRC）在内的各种恶性肿瘤的发病机理有关。泛素结构域含1（UBTD1），泛素样蛋白质,在某些癌症类型中调节UPS介导的蛋白质降解和肿瘤进展。然而,UBTD1的生物学功能和机制还远未得到很好的阐明，其在《儿童权利公约》中的作用尚未得到探讨。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，并发现UBTD1在癌组织中的表达明显高于癌旁正常组织。较高的UBTD1表达与较差的生存率和更多的淋巴结转移显著相关。UBTD1的过表达可以促进，而敲低可以抑制CRC细胞的增殖和迁移，分别。RNA-seq和蛋白质组学表明c-Myc是UBTD1的重要下游靶标。代谢组学显示糖酵解通路的产品在UBTD1过表达细胞中显著增多。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促进CRC细胞糖酵解，UBTD1过表达后乳酸产生和葡萄糖摄取增加证明。机械上,UBTD1通过与E3连接酶β转导蛋白重复序列蛋白（β-TrCP）结合延长了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，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途径上调糖酵解促进CRC进展，提示其作为CRC预后生物标志物和治疗靶点的潜力。
