Wang Jin-Bao, Ding Shi-Lin, Liu Xiao-Song, Yu Tianren, Wu Zeng-An, Li Yu-Xiang
Department of Surgery, Wangjing Hospital of China Academy of Chinese Medical Sciences, Beijing, 100102, China.
Curr Mol Med. 2025;25(1):27-36. doi: 10.2174/0115665240271525231112121008.
Colorectal cancer (CRC) is a malignant tumor. Slug has been found to display a key role in diversified cancers, but its relevant regulatory mechanisms in CRC development are not fully explored.
Hence, exploring the function and regulatory mechanisms of Slug is critical for the treatment of CRC.
Protein expressions of Slug, N-cadherin, E-cadherin, Snail, HIF-1α, SUMO- 1, Drp1, Opa1, Mfn1/2, PGC-1α, NRF1, and TFAM were measured through western blot. To evaluate the protein expression of Slug and SUMO-1, an immunofluorescence assay was used. Cell migration ability was tested through transwell assay. The SUMOylation of Slug was examined through CO-IP assay.
Slug displayed higher expression and facilitated tumor metastasis in CRC. In addition, hypoxia treatment was discovered to upregulate HIF-1α, Slug, and SUMO-1 levels, as well as induce Slug SUMOylation. Slug SUMOylation markedly affected mitochondrial biosynthesis, fusion, and mitogen-related protein expression levels to trigger mitochondrial stress. Additionally, the induced mitochondrial stress by hypoxia could be rescued by Slug inhibition and TAK-981 treatment.
Our study expounded that hypoxia affects mitochondrial stress and facilitates tumor metastasis of CRC through Slug SUMOylation.
结直肠癌（CRC）是一种恶性肿瘤。已发现Slug在多种癌症中发挥关键作用，但其在CRC发生发展中的相关调控机制尚未完全阐明。
因此，探究Slug的功能及调控机制对CRC的治疗至关重要。
通过蛋白质免疫印迹法检测Slug、N-钙黏蛋白、E-钙黏蛋白、Snail、低氧诱导因子-1α（HIF-1α）、小泛素样修饰蛋白1（SUMO-1）、动力相关蛋白1（Drp1）、视神经萎缩蛋白1（Opa1）、线粒体融合蛋白1/2（Mfn1/2）、过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）、核呼吸因子1（NRF1）和线粒体转录因子A（TFAM）的蛋白表达。采用免疫荧光法评估Slug和SUMO-1的蛋白表达。通过Transwell实验检测细胞迁移能力。采用免疫共沉淀实验检测Slug的SUMO化修饰。
Slug在CRC中表达较高并促进肿瘤转移。此外，发现低氧处理可上调HIF-1α、Slug和SUMO-1水平，并诱导Slug的SUMO化修饰。Slug的SUMO化修饰显著影响线粒体生物合成、融合及有丝分裂相关蛋白表达水平，从而引发线粒体应激。此外，低氧诱导的线粒体应激可通过抑制Slug和TAK-981处理得到缓解。
我们的研究阐明，低氧通过Slug的SUMO化修饰影响线粒体应激并促进CRC的肿瘤转移。
