Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 120-750, Korea.
Functional Morphometry II, Institute Pasteur Korea, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, Korea.
Cell Death Differ. 2019 May;26(5):812-825. doi: 10.1038/s41418-018-0153-0. Epub 2018 Jul 13.
Cathepsin S (CTSS) is a cysteine protease that is thought to play a role in many physiological and pathological processes including tumor growth, angiogenesis, and metastasis; it has been identified as a radiation response gene. Here, we examined the role of CTSS in regulating the DNA damage response in breast cancer cells. Activating CTSS (producing the cleavage form of the protein) by radiation induced proteolytic degradation of BRCA1, which ultimately suppressed DNA double-strand break repair activity. Depletion of CTSS by RNAi or expression of a mutant type of CTSS enhanced the protein stability of BRCA1 by inhibiting its ubiquitination. CTSS interacted with the BRCT domain of BRCA1 and facilitated ubiquitin-mediated proteolytic degradation of BRCA1, which was tightly associated with decreased BRCA1-mediated DNA repair activity. Treatment with a pharmacological CTSS inhibitor inhibited proteolytic degradation of BRCA1 and restored BRCA1 function. Depletion of CTSS by shRNA delayed tumor growth in a xenograft mouse model, only in the presence of functional BRCA1. Spontaneously uced rat mammary tumors and human breast cancer tissues with high levels of CTSS expression showed low BRCA1 expression. From these data, we suggest that CTSS inhibition is a good strategy for functional restoration of BRCA1 in breast cancers with reduced BRCA1 protein stability.
组织蛋白酶 S（CTSS）是一种半胱氨酸蛋白酶，被认为在许多生理和病理过程中发挥作用，包括肿瘤生长、血管生成和转移；它已被确定为辐射反应基因。在这里，我们研究了 CTSS 在调节乳腺癌细胞中 DNA 损伤反应中的作用。辐射通过激活 CTSS（产生蛋白质的裂解形式）诱导 BRCA1 的蛋白水解降解，最终抑制 DNA 双链断裂修复活性。通过 RNAi 耗竭 CTSS 或表达突变型 CTSS 通过抑制其泛素化来增强 BRCA1 的蛋白稳定性。CTSS 与 BRCA1 的 BRCT 结构域相互作用，并促进 BRCA1 的泛素介导的蛋白水解降解，这与 BRCA1 介导的 DNA 修复活性降低密切相关。用药理学 CTSS 抑制剂抑制 BRCA1 的蛋白水解降解并恢复 BRCA1 功能。用 shRNA 耗竭 CTSS 仅在存在功能性 BRCA1 的情况下延迟异种移植小鼠模型中的肿瘤生长。自发诱导的大鼠乳腺肿瘤和高 CTSS 表达水平的人类乳腺癌组织显示 BRCA1 表达水平降低。从这些数据中，我们认为 CTSS 抑制是恢复具有降低 BRCA1 蛋白稳定性的乳腺癌中 BRCA1 功能的一种很好的策略。
