乙酰化
泛素连接酶
泛素
癌症研究
磷酸化
化学
组蛋白
CD44细胞
丝氨酸
干细胞
细胞生物学
生物
细胞
生物化学
基因
作者
Xinyue Zhou,Xiaoqi Liu,Xueying Wan,Ming Xu,Rui Wang,Dan Yang,Meixi Peng,Ting Jin,Rui Tang,Manran Liu,Yixuan Hou
标识
DOI:10.1016/j.bbrc.2023.149243
摘要
Cancer stem cells (CSCs), as parts of tumor initiation cells, play a crucial role to tumorigenesis, development and recurrence. However, the complicated mechanisms of CSCs to adapt to tumor microenvironment and its stemness maintenance remains unclear. Here, we show that oxidized ATM, a hypoxia-activated cytoplasm ATM, acts a novel function to maintain CSC stemness in triple-negative breast cancer cells (BCSCs) via regulating histone H4 acetylation. Mechanistically, oxidized ATM phosphorylates TRIM21 (a E3 ubiquitin ligase) serine 80 and serine 469. Serine 80 phosphorylation of TRIM21 is essential for the ubiquitination activity of TRIM21. TRIM21 binds with SIRT1 (one of deacetylase), resulting in ubiquitylation-mediated degradation of SIRT1. The reduced SIRT1 leads to increase of histone H4 acetylation, thus facilitating CSC-related gene expression. Clinical data verify that high level of ATM in breast tumors is positively correlated with malignant grade, and is closely related with low SIRT1, high p-TRIM21, and high CD44 expression. In conclusion, our study provides a novel mechanism by which oxidized ATM governing BCSCs stemness and reveals an important link among oxidized ATM, histone acetylation, and BCSCs maintenance.
科研通智能强力驱动
Strongly Powered by AbleSci AI