Chronic Inflammation Pathway NF-κB Cooperates with Epigenetic Reprogramming to Drive the Malignant Progression of Glioblastoma.
Chronic Inflammation Pathway NF-κB Cooperates with Epigenetic Reprogramming to Drive the Malignant Progression of Glioblastoma.
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慢性炎症通路 NF-κB 与表观遗传重编程合作驱动胶质母细胞瘤的恶性进展。
DOI：
10.7150/ijbs.73749
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发表时间：
2022
影响因子：
9.2
通讯作者：
Jin B
中科院分区：
文献类型：
--
作者：
Lin K;Gao W;Chen N;Yang S;Wang H;Wang R;Xie F;Meng J;Lam EW;Li S;Cheng W;Chen P;Wu H;Yan J;Jin D;Jin B
如果没有有效的靶向治疗策略，胶质母细胞瘤仍然是无法治愈的，中位生存期只有15个月。慢性炎症和表观遗传重编程都是癌症的标志。然而，它们在胶质母细胞瘤中的合作机制和后果尚不清楚。在这里，我们发现慢性炎症通过NF-κB途径调控胶质母细胞瘤中的H3K27me3重编程，以靶向EZH2。作为慢性炎症的重要介质，规范的NF-κB信号通路特异性指导H3K27me3的表达和再分布，而不是H3K4me3、H3K9me3和H3K36me3。通过RNA-seq筛选，我们发现EZH2是控制胶质瘤形成过程中炎症引发的表观遗传重编程的关键甲基转移酶。从机制上讲，NF-κB通过激活EZH2的转录，选择性地驱动EZH2的表达，从而导致H3K27me3表达和分布的全局变化。此外，我们发现NF-κB和EZH2共同激活的临床结果最差，NF-κB和EZH2可以准确地对胶质母细胞瘤的风险进行分子分层。值得注意的是，NF-κB可以以多种方式潜在地与EZH2合作，最重要的是，我们证明了NF-κB和EZH2联合抑制诱导的癌细胞的协同效应，这两者在胶质母细胞瘤中经常过度激活。总之，我们揭示了胶质母细胞瘤中慢性炎症和表观遗传重编程之间的功能合作，通过抑制剂的联合靶向，保证了安全性和可用性，为有效治疗这种致命疾病提供了强有力的策略。
Without an effective strategy for targeted therapy, glioblastoma is still incurable with a median survival of only 15 months. Both chronic inflammation and epigenetic reprogramming are hallmarks of cancer. However, the mechanisms and consequences of their cooperation in glioblastoma remain unknown. Here, we discover that chronic inflammation governs H3K27me3 reprogramming in glioblastoma through the canonical NF-κB pathway to target EZH2. Being a crucial mediator of chronic inflammation, the canonical NF-κB signalling specifically directs the expression and redistribution of H3K27me3 but not H3K4me3, H3K9me3 and H3K36me3. Using RNA-seq screening to focus on genes encoding methyltransferases and demethylases of histone, we identify EZH2 as a key methyltransferase to control inflammation-triggered epigenetic reprogramming in gliomagenesis. Mechanistically, NF-κB selectively drives the expression of EZH2 by activating its transcription, consequently resulting in a global change in H3K27me3 expression and distribution. Furthermore, we find that co-activation of NF-κB and EZH2 confers the poorest clinical outcome, and that the risk for glioblastoma can be accurately molecularly stratified by NF-κB and EZH2. It is notable that NF-κB can potentially cooperate with EZH2 in more than one way, and most importantly, we demonstrate a Synergistic effect of cancer cells induced by combinatory inhibition of NF-κB and EZH2, which both are frequently over-activated in glioblastoma. In summary, we uncover a functional cooperation between chronic inflammation and epigenetic reprogramming in glioblastoma, combined targeting of which by inhibitors guaranteed in safety and availability furnishes a potent strategy for effective treatment of this fatal disease.
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影响因子：
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作者：
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