Targeting Cooperation of Chronic Inflammation with Epigenetic Reprogramming Triggers a Synthetic Lethality in Glioblastoma Multiforme
Research Square (Research Square)(2022)
摘要
Abstract Background Without an effective strategy for targeted therapy, glioblastoma multiforme (GBM) 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 GBM remain unknown. Methods Western blotting was carried out to detect levels of various histone modifications affected by NF-κB signalling. Then, RNA-seq was used to screen genes encoding methyltransferases and demethylases of histone. Dual-luciferase reporter gene and ChIP assays were performed to determine whether NF-κB activates the transcription of EZH2. Subsequently, ChIP-seq and RT-qPCR were performed to explore the variety of H3K27me3 distribution. Expression levels of p65 and EZH2 in glioma samples were evaluated by IHC, and tumorigenicity assays (in vitro and in vivo) were performed to demonstrate the effects of combining NF-κBi and EZH2i on GBM progression. Results We discovered that chronic inflammation governs H3K27me3 reprogramming in GBM 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. Then, we identified 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 of 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 GBM 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 demonstrated a synthetic lethality of cancer cells induced by combinatory inhibition of NF-κB and EZH2, which both are frequently over-activated in GBM. Conclusions We uncover a functional cooperation between chronic inflammation and epigenetic reprogramming in GBM. Thus, combined targeting of NF-κB and EZH2 by inhibitors can be a potent strategy for the effective treatment of this fatal disease.
更多查看译文
关键词
epigenetic reprogramming triggers,glioblastoma multiforme,synthetic lethality
AI 理解论文
溯源树
样例
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要