雷布
EZH2型
活性氧
生物
癌症研究
表型
甲基化
细胞生物学
遗传学
NFKB1型
转录因子
基因
作者
Lynnette Koh,Qing You Pang,Wisna Novera,See Wee Lim,Yuk Kien Chong,Jinyue Liu,Samantha Ya Lyn Ang,Ron Weng Yee Loh,Huilin Shao,Jianhong Ching,Yulan Wang,Stephen Yip,Patrick Tan,Shang Li,David C.Y. Low,Anne M. Phelan,Gabriel Rosser,Nguan Soon Tan,Carol Tang,Beng Ti Ang
出处
期刊:Neuro-oncology
[Oxford University Press]
日期:2024-10-07
标识
DOI:10.1093/neuonc/noae206
摘要
Abstract Background EZH2, well-known for its canonical methyltransferase activity in transcriptional repression in many cancers including glioblastoma (GBM), has an understudied non-canonical function critical for sustained tumor growth. Recent GBM consortial efforts reveal complex molecular heterogeneity for which therapeutic vulnerabilities correlated with subtype stratification remain relatively unexplored. Current enzymatic EZH2 inhibitors (EZH2inh) targeting its canonical SET domain show limited efficacy and lack durable response, suggesting that underlying differences in the non-canonical pathway may yield new knowledge. Here, we unveiled dual roles of the EZH2 CXC domain in therapeutically-distinct, reactive oxygen species (ROS)-stratified tumors. Methods We analyzed differentially expressed genes between ROS classes by examining cis-regulatory elements as well as clustering of activities and pathways to identify EZH2 as the key mediator in ROS-stratified cohorts. Pull-down assays and CRISPR knockout of EZH2 domains were used to dissect the distinct functions of EZH2 in ROS-stratified GBM cells. The efficacy of NF-κB-inducing kinase inhibitor (NIKinh) and standard-of-care temozolomide was evaluated using orthotopic patient-derived GBM xenografts. Results In ROS(+) tumors, CXC-mediated co-interaction with RelB drives constitutive activation of non-canonical NF-κB2 signaling, sustaining the ROS(+) chemoresistant phenotype. In contrast, in ROS(-) subtypes, PRC2 methyltransferase activity represses canonical NF-κB. Addressing the lack of EZH2inh targeting its non-methyltransferase roles, we utilized a brain-penetrant NIKinh that disrupts EZH2-RelB binding, consequently prolonging survival in orthotopic ROS(+)-implanted mice. Conclusion Our findings highlight the functional dichotomy of the EZH2 CXC domain in governing ROS-stratified therapeutic resistance, thereby advocating for the development of therapeutic approaches targeting its non-canonical activities and underscoring the significance of patient stratification methodologies.
科研通智能强力驱动
Strongly Powered by AbleSci AI