Precision Medicine Research Center, Advanced Institute of Convergence Technology, Seoul National University, Suwon, Gyeonggi-do, 16229, Republic of Korea.
Department of Biomedical Science, College of Life Science, CHA University, Seongnam City, Gyeonggi-do, 463-400, Republic of Korea.
Nat Commun. 2019 Dec 20;10(1):5805. doi: 10.1038/s41467-019-13852-5.
The development of triple-negative breast cancer (TNBC) negatively impacts both quality of life and survival in a high percentage of patients. Here, we show that RING finger protein 208 (RNF208) decreases the stability of soluble Vimentin protein through a polyubiquitin-mediated proteasomal degradation pathway, thereby suppressing metastasis of TNBC cells. RNF208 was significantly lower in TNBC than the luminal type, and low expression of RNF208 was strongly associated with poor clinical outcomes. Furthermore, RNF208 was induced by 17β-estradiol (E2) treatment in an estrogen receptor alpha (ΕRα)-dependent manner. Overexpression of RNF208 suppresses tumor formation and lung metastasis of TNBC cells. Mechanistically, RNF208 specifically polyubiquitinated the Lys97 residue within the head domain of Vimentin through interaction with the Ser39 residue of phosphorylated Vimentin, which exists as a soluble form, eventually facilitating proteasomal degradation of Vimentin. Collectively, our findings define RNF208 as a negative regulator of soluble Vimentin and a prognostic biomarker for TNBC cells.
三阴性乳腺癌（TNBC）的发展对大多数患者的生活质量和生存产生负面影响。在这里，我们表明 RING 指蛋白 208（RNF208）通过多泛素化介导的蛋白酶体降解途径降低可溶性波形蛋白的稳定性，从而抑制 TNBC 细胞的转移。RNF208 在 TNBC 中的表达明显低于腔型，RNF208 的低表达与不良临床结局密切相关。此外，RNF208 被 17β-雌二醇（E2）以雌激素受体α（ΕRα）依赖性方式诱导。RNF208 的过表达抑制 TNBC 细胞的肿瘤形成和肺转移。在机制上，RNF208 通过与磷酸化波形蛋白的 Ser39 残基相互作用，特异性地多泛素化波形蛋白头部结构域中的 Lys97 残基，从而促进波形蛋白的蛋白酶体降解。总之，我们的研究结果将 RNF208 定义为可溶性波形蛋白的负调节剂和 TNBC 细胞的预后生物标志物。
