EZH2功能性二分法中的活性氧分离的胶质母细胞瘤
EZH2 functional dichotomy in reactive oxygen species-stratified glioblastoma
影响因子:13.40000
分区:医学1区 Top / 临床神经病学1区 肿瘤学1区
发表日期:2025 Feb 10
作者:
Lynnette Wei Hsien 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 Chyi Yeu Low, Anne Phelan, Gabriel Rosser, Nguan Soon Tan, Carol Tang, Beng Ti Ang
摘要
Zeste同源物2（EZH2）的增强子，以其在包括胶质母细胞瘤（GBM）在内的许多癌症中的转录抑制作用中的规范甲基转移酶活性而闻名，其研究对持续肿瘤生长至关重要。 GBM最近的联盟努力揭示了复杂的分子异质性，与亚型分层相关的治疗脆弱性仍然相对尚未探索。当前针对其规范SU（VAR）3-9，添加器的增强子和Trithorax结构域的酶促EZH2抑制剂（EZH2INH）显示出有限的疗效和缺乏持久的响应，这表明在非宗教途径的基本差异可能会产生新的知识。在这里，我们揭示了EZH2 CXC结构域在治疗不同的，活性氧（ROS）延伸的肿瘤中的双重作用。我们通过检查顺式调节元素以及聚类的活动和途径来识别EZH2在ROS类中进行了差异，从而分析了ROS类之间的差异表达基因，以将EZH2识别为Ros-Stratified In Rostratified Intratified In Rosstratified Intratified。使用EZH2结构域的下拉测定和CRISPR敲除，以剖析EZH2在ROS分层的GBM细胞中的不同功能。使用原位的患者衍生的GBM Xenografts.in ROS（+）肿瘤评估了NF-κB诱导激酶抑制剂（Nikinh）和护理标准替莫唑胺的功效，CXC介导的与RELB介导的relb驱动器驱动器驱动型nf-ky-κB2信号（ROS）的功效（+）的肿瘤相互交互。相反，在ROS（ - ）亚型中，PolyComb抑制复合物2甲基转移酶活性抑制剂抑制规范NF-κB。解决了针对其非甲基转移酶角色的EZH2INH缺乏的问题，我们利用了脑培养尼基尼的尼基尼，破坏了Ezh2-Relb结合，因此在正位型ROS（+）中延长了生存率。倡导针对其非规范活动的治疗方法的发展，并强调患者分层方法的重要性。
Abstract
Enhancer of zeste homolog 2 (EZH2), well known for its canonical methyltransferase activity in transcriptional repression in many cancers including glioblastoma (GBM), has an understudied noncanonical 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 su(var)3-9, enhancer-of-zeste and trithorax domain show limited efficacy and lack durable response, suggesting that underlying differences in the noncanonical pathway may yield new knowledge. Here, we unveiled dual roles of the EZH2 CXC domain in therapeutically distinct, reactive oxygen species (ROS)-stratified tumors.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.In ROS(+) tumors, CXC-mediated co-interaction with RelB drives constitutive activation of noncanonical NF-κB2 signaling, sustaining the ROS(+) chemoresistant phenotype. In contrast, in ROS(-) subtypes, Polycomb Repressive Complex 2 methyltransferase activity represses canonical NF-κB. Addressing the lack of EZH2inh targeting its nonmethyltransferase roles, we utilized a brain-penetrant NIKinh that disrupts EZH2-RelB binding, consequently prolonging survival in orthotopic ROS(+)-implanted mice.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 noncanonical activities and underscoring the significance of patient stratification methodologies.