Dataset Information

Chronic Inflammation Pathway NF-κB Cooperates with Epigenetic Reprogramming to Drive the Malignant Progression of Glioblastoma.

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.

SUBMITTER: Lin K

PROVIDER: S-EPMC9576505 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Chronic Inflammation Pathway NF-κB Cooperates with Epigenetic Reprogramming to Drive the Malignant Progression of Glioblastoma.

Lin Kefeng K Gao Wenli W Chen Ning N Yang Shuyao S Wang Han H Wang Ran R Xie Fang F Meng Jiaqi J Lam Eric W-F EW Li Suyi S Cheng Wei W Chen Puxiang P Wu Hongjin H Yan Jinsong J Jin Di D Jin Bilian B

International journal of biological sciences 20220921 15

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 can ...[more]

PMID: 36263173

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Project description:BackgroundRecent studies have highlighted the significant role of the NF-κB signaling pathway in the initiation and progression of cancer. Furthermore, long noncoding RNAs (lncRNAs) have been identified as pivotal regulators in sustaining the NF-κB signaling pathway's functionality. Despite these findings, the underlying molecular mechanisms through which lncRNAs influence the NF-κB pathway remain largely unexplored.MethodsBioinformatic analyses were utilized to investigate the differential expression and prognostic significance of XTP6. The functional roles of XTP6 were further elucidated through both in vitro and in vivo experimental approaches. To estimate the interaction between XTP6 and NDH2, RNA pulldown and RNA Immunoprecipitation (RIP) assays were conducted. The connection between XTP6 and the IκBα promoter was examined using Chromatin Isolation by RNA Purification (ChIRP) assays. Additionally, Chromatin Immunoprecipitation (ChIP) assays were implemented to analyze the binding affinity of c-myc to the XTP6 promoter, providing insights into the regulatory mechanisms at play.ResultsXTP6 was remarkedly upregulated in glioblastoma multiforme (GBM) tissues and was connected with adverse prognosis in GBM patients. Our investigations revealed that XTP6 can facilitate the malignant progression of GBM both in vitro and in vivo. Additionally, XTP6 downregulated IκBα expression by recruiting NDH2 to the IκBα promoter, which resulted in elevated levels of H3K27me3, thereby reducing the transcriptional activity of IκBα. Moreover, the progression of GBM was further driven by the c-myc-mediated upregulation of XTP6, establishing a positive feedback loop with IκBα that perpetuated the activation of the NF-κB signaling pathway. Notably, the application of an inhibitor targeting the NF-κB signaling pathway effectively inhibited the continuous activation induced by XTP6, leading to a significant reduction in tumor formation in vivo.ConclusionThe results reveal that XTP6 unveils an innovative epigenetic mechanism instrumental in the sustained activation of the NF-κB signaling pathway, suggesting a promising therapeutic target for the treatment of GBM.

Project description:BackgroundRegulator of cullins 1 (ROC1) is an important catalytic subunit of cullin-RING E3 ligase. Nuclear factor-kappa B (NF-κB) signaling is closely related to tumor invasion and metastasis. Earlier, we reported that ROC1 was associated with a poor prognosis in patients with bladder cancer (BCa). However, it is unclear whether ROC1 is involved in the NF-κB signaling associated with malignant BCa progression.MethodsThe expression of ROC1 and p65 in bladder cancer and paracancerous tissues were detected by immunohistochemistry (IHC). Pearson correlation was used to assess correlation between ROC1 and p65 protein expressions. The wound-healing and transwell assays were used to monitor cell invasion and migration. The effect of ROC1 on the expression of key proteins in the NF-κB signaling was determined by immunofluorescence and western blot (WB). Cycloheximide (CHX), MG132 and immunoprecipitation assays were used to evaluate the effect of ROC1 on the ubiquitination of phosphorylated inhibitor of kappa B alpha (p-IκBα). A lung metastasis mouse model was generated to detect the role of ROC1 in tumor metastasis.ResultsWe found that ROC1 was up-regulated in BCa tissues and cell lines, and high ROC1 levels were positively correlated with higher tumour grade, lymph node metastasis, distant metastasis and poor prognosis. Linear-regression analysis showed significant a Pearson correlation between ROC1 and nuclear p65 expression in BCa tissue microarray (TMA) samples. Functional studies demonstrated that ROC1 promoted BCa cell invasion and migration. In vitro and in vivo experiments showed that ROC1 activated NF-κB signaling by enhancing the ubiquitination of p-IκBα, which caused p65 nuclear translocation and promoted the transcription of some metastasis-related target genes, such as urokinase-type plasminogen activator receptor (uPAR), intracellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), and matrix metalloproteinase 9 (MMP9), resulting in promoting BCa metastasis.ConclusionROC1 plays an important role in the progression of BCa and serves as a potential diagnostic and therapeutic target for patients with BCa.

Dataset Information

Chronic Inflammation Pathway NF-κB Cooperates with Epigenetic Reprogramming to Drive the Malignant Progression of Glioblastoma.

Publications

Chronic Inflammation Pathway NF-κB Cooperates with Epigenetic Reprogramming to Drive the Malignant Progression of Glioblastoma.

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