PO.ET09.02 · 实验与分子治疗
BET结构域在IDH1 R132H/p53突变/ATRX缺失星形细胞瘤恶性进展中的功能
BET domain functions in IDH1 R132H /p53 mut /ATRX loss astrocytoma malignancy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
II/III级星形细胞瘤是年轻成年人中最常见的原发性脑癌，并越来越被认识为表观遗传驱动的肿瘤。其特征性的突变背景——IDH1 R132H、p53突变和ATRX缺失（三重突变）——建立了一种高甲基化和染色质紊乱的状态，重塑了转录网络，并造成了不同于原发性胶质母细胞瘤（GBM）的独特治疗易感性。这种表观遗传改变的格局提示，三重突变星形细胞瘤的肿瘤进展和治疗反应强烈受到可通过药物靶向的染色质相关机制的影响。BET蛋白作为表观遗传阅读器，通过结合乙酰化组蛋白并将主转录因子招募至染色质来调控基因转录，然而BET家族各个成员及其溴结构域的具体作用仍知之甚少。对TCGA数据集的分析显示，与IDH1野生型胶质瘤相比，临床三重突变胶质瘤中BRD3和BRD2的表达显著升高。与此一致，免疫印迹分析显示BRD3表达由三重突变诱导，并在电离辐射（IR）和替莫唑胺（TMZ）处理后进一步增强。在功能上，使用泛BET抑制剂（JQ1、OTX015）或溴结构域1（BD1）选择性抑制剂GSK778——但非溴结构域2（BD2）选择性抑制剂GSK620——抑制BET蛋白，可显著降低三重突变胶质瘤细胞生长，损害神经球自我更新，并增强TMZ诱导的细胞死亡。此外，BD1抑制显著抑制由三重突变、IR/TMZ处理或IFN-gamma刺激所触发的PD-L1诱导。在机制上，我们发现BD1抑制降低YAP1和TAZ的表达并破坏YAP1/TAZ转录信号，而BD2抑制则不然。这些发现确定了一个BD1依赖的转录网络，其调控星形细胞瘤细胞表型并促成免疫抑制性微环境。靶向BD1通过同时抑制肿瘤细胞内在的致癌信号（例如YAP1/TAZ信号）并重塑免疫抑制性微环境，代表了一种合理的治疗策略。
查看英文原文 English abstract
Grade II/III astrocytomas are the most common primary brain cancer in young adults and are increasingly recognized as epigenetically driven tumors. Their defining mutational background IDH1 R132H ,p53 mut , and ATRX loss (triple-mut) establishes a hypermethylated and chromatin-disrupted state that reshapes transcriptional networks and creates unique therapeutic vulnerabilities distinct from primary glioblastoma (GBM). This epigenetically altered landscape suggests that tumor progression and treatment response in triple-mut astrocytoma are strongly influenced by chromatin-based mechanisms that can be targeted pharmacologically. BET proteins as epigenetic readers that regulate gene transcription by binding acetylated histone and recruiting master transcription factors to chromatin, yet the specific roles of individual BET family members and their bromodomains remain poorly understood. Analysis of TCGA datasets revealed that BRD3 and BRD2 expressions are significantly elevated in clinical triple-mut gliomas compared to IDH1 wild-type gliomas. Consistently, the immunoblot analysis showed that BRD3 expression is induced by the triple-mut and further enhanced by ionizing radiation (IR) and temozolomide (TMZ) treatment . Functionally, inhibition of BET proteins using either pan-BET inhibitors (JQ1, OTX015) or bromodomain 1 (BD1)-selective inhibitor GSK778-but not bromodomain 2 (BD2)-selective inhibitor GSK620- markedly reduces triple-mut glioma cell growth and impairs neurosphere self-renewal , and enhances TMZ-induced cell death . Moreover, BD1 inhibition significantly suppresses PD-L1 induction triggered by the triple-mut, IR/TMZ treatment, or IFN-gamma stimulation. Mechanistically, we find that BD1 inhibition decreases YAP1 and TAZ expression and disrupts YAP1/TAZ transcriptional signaling, whereas BD2 inhibition does not. These findings identify a BD1-dependent transcriptional network that regulates astrocytoma cell phenotype and contributes to an immunosuppressive microenvironment. Targeting BD1 represents a rational therapeutic strategy by simultaneously suppressing tumor cell-intrinsic oncogenic signaling (e.g.,YAP1/TAZ signaling) and reshaping the immunosuppressive microenvironment.
利益披露 Disclosure
Y. Li, None.