ISSN: 1449-2288International Journal of Biological Sciences
Global reach, higher impact
Int J Biol Sci 2022; 18(15):5770-5786. doi:10.7150/ijbs.73749 This issue Cite
Research Paper
Chronic Inflammation Pathway NF-κB Cooperates with Epigenetic Reprogramming to Drive the Malignant Progression of Glioblastoma
1. Institute of Cancer Stem Cell; Liaoning Key Laboratory of Nucleic Acid Biology, Dalian Medical University, Dalian 116044, Liaoning, China.
2. Department of Hematology; Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine; Liaoning Medical Center for Hematopoietic Stem Cell Transplantation; Dalian Key Laboratory of Hematology; Diamond Bay Institute of Hematology, Second Hospital of Dalian Medical University, Dalian 116044, China.
3. Boao International Hospital, Shanghai University of Traditional Chinese Medicine, Qionghai 571734, Hainan, China.
4. Department of Obstetrics and Gynecology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China.
#These authors contributed equally.
Abstract
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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