Department of Breast Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, 150 Haping Road, Harbin, Heilongjiang Province 150040, China.
Research Center for Pharmacoinformatics (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy, Harbin Medical University, 157 Baojian Road, Harbin, Heilongjiang Province 150081, China.
Cell Rep. 2024 Jul 23;43(7):114507. doi: 10.1016/j.celrep.2024.114507. Epub 2024 Jul 13.
The oxidative-stress-related protein Kelch-like ECH-associated protein 1 (KEAP1) is a substrate articulator of E3 ubiquitin ligase, which plays an important role in the ubiquitination modification of proteins. However, the function of KEAP1 in breast cancer and its impact on the survival of patients with breast cancer remain unclear. Our study demonstrates that KEAP1, a positive prognostic factor, plays a crucial role in regulating cell proliferation, apoptosis, and cell cycle transition in breast cancer. We investigate the underlying mechanism using human tumor tissues, high-throughput detection technology, and a mouse xenograft tumor model. KEAP1 serves as a key regulator of cellular metabolism, the reprogramming of which is one of the hallmarks of tumorigenesis. KEAP1 has a significant effect on mitochondrial biogenesis and oxidative phosphorylation by regulating HSPA9 ubiquitination and degradation. These results suggest that KEAP1 could serve as a potential biomarker and therapeutic target in the treatment of breast cancer.
氧化应激相关蛋白 Kelch 样 ECH 相关蛋白 1（KEAP1）是 E3 泛素连接酶的底物衔接蛋白，在蛋白质的泛素化修饰中发挥重要作用。然而，KEAP1 在乳腺癌中的功能及其对乳腺癌患者生存的影响尚不清楚。我们的研究表明，作为一个阳性预后因素的 KEAP1，在调节乳腺癌细胞增殖、凋亡和细胞周期转换方面发挥着关键作用。我们使用人肿瘤组织、高通量检测技术和小鼠异种移植肿瘤模型来研究其潜在机制。KEAP1 是细胞代谢的关键调节剂，代谢重编程是肿瘤发生的标志之一。KEAP1 通过调节 HSPA9 的泛素化和降解，对线粒体生物发生和氧化磷酸化有显著影响。这些结果表明，KEAP1 可能成为治疗乳腺癌的潜在生物标志物和治疗靶点。
