泛蛋白UBTD1通过稳定c-Myc上调糖酵解促进结直肠癌进展

The ubiquitin-like protein UBTD1 promotes colorectal cancer progression by stabilizing c-Myc to upregulate glycolysis

Cell Death & Disease

影响因子:9.6

分区:生物学1区 Top / 细胞生物学2区

发表日期:2024 Jul 13

作者: Liqin Zhao, Nuoya Yu, Yujia Zhai, Yanan Yang, Yixuan Wang, Yue Yang, Zhe Gong, Yanqiu Zhang, Xiaowei Zhang, Weijian Guo

DOI: 10.1038/s41419-024-06890-5

摘要

泛素-蛋白酶体系统（UPS）功能障碍涉及多种恶性肿瘤的发病机制，包括结直肠癌（CRC）。泛素样蛋白质UBTD1（ubiquitin domain containing 1）调控UPS介导的蛋白降解和某些癌症类型的肿瘤进展。然而，UBTD1的生物学功能及其机制尚未被充分阐明，其在CRC中的作用也尚未得到探索。在本研究中，我们分析了CRC患者的临床信息和UBTD1表达数据，发现癌组织中的UBTD1表达显著高于邻近正常组织。UBTD1高表达与较差的生存率及更多的淋巴结转移显著相关。UBTD1过表达可促进CRC细胞的增殖和迁移，而敲低则能抑制。RNA测序和蛋白组学分析显示，c-Myc是UBTD1的重要下游靶点。代谢组学显示，UBTD1过表达细胞中糖酵解途径的产物显著增加。在体外实验中，我们验证了UBTD1通过调控c-Myc上调c-Myc蛋白，促进CRC细胞的增殖和迁移。UBTD1促使CRC细胞的糖酵解，表现为UBTD1过表达后乳酸产生和葡萄糖摄取增加。从机制上看，UBTD1通过与E3连接酶β-转导素重复含量蛋白（β-TrCP）结合，延长c-Myc蛋白的半衰期，从而上调糖酵解速率限制酶己糖激酶II（HK2）的表达，增强糖酵解并促进CRC进展。总结而言，我们的研究揭示了UBTD1通过β-TrCP/c-Myc/HK2通路上调糖酵解，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。

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.