Oxidized ATM governs stemness of breast cancer stem cell through regulating ubiquitylation and acetylation switch

作者全名："Zhou, Xinyue; Liu, Xiaoqi; Wan, Xueying; Xu, Ming; Wang, Rui; Yang, Dan; Peng, Meixi; Jin, Ting; Tang, Rui; Liu, Manran; Hou, Yixuan"

作者地址："[Zhou, Xinyue; Wan, Xueying; Xu, Ming; Wang, Rui; Yang, Dan; Peng, Meixi; Jin, Ting; Tang, Rui; Liu, Manran] Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, Chongqing 400016, Peoples R China; [Liu, Xiaoqi] Chongqing Med Univ, Pediat Res Inst,Childrens Hosp, Natl Clin Res Ctr Child Hlth & Disorders, Minist Educ,Key Lab Child Dev & Disorders,Chongqin, Chongqing 400014, Peoples R China; [Hou, Yixuan] Chongqing Med Univ, Expt Teaching Ctr Basic Med Sci, Chongqing 400016, Peoples R China; [Hou, Yixuan] Chongqing Med Univ, Expt Teaching Ctr Basic Med Sci, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China"

通信作者："Hou, YX (通讯作者)，Chongqing Med Univ, Expt Teaching Ctr Basic Med Sci, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China."

来源：BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001165393300001

JCR分区：Q2

影响因子：3.1

年份：2024

卷号：691

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Oxidized -ATM; Hypoxia; SIRT1; TRIM21

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."

基金机构："National Natural Science Foundation of China [NSFC 81472476, NSFC 81874199, 81773078]"

基金资助正文："This work was supported in part by National Natural Science Foundation of China (NSFC 81472476, NSFC 81874199 and 81773078)."