Tumor immune microenvironment exerts a profound effect on the population of infiltrating immune cells. Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) is frequently overexpressed in a variety of cells, particularly during inflammation and tissue injury. However, its function in cancer and immunity remains enigmatic. In this study, we find that TIMP1 is substantially up-regulated during tumorigenesis through analyzing cancer bioinformatics databases, which is further confirmed by IHC tissue microarrays of clinical samples. The TIMP1 level is significantly increased in lymphocytes infiltrating the tumors and correlated with cancer progression, particularly in GBM. Notably, we find that the transcriptional factor Sp1 binds to the promoter of TIMP1 and triggers its expression in GBM. Together, our findings suggest that the Sp1-TIMP1 axis can be a potent biomarker for evaluating immune cell infiltration at the tumor sites and therefore, the malignant progression of GBM.

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.

Long noncoding RNAs (lncRNAs) are engaged in many physiological and pathological processes, including stem cell differentiation, growth, and development, senescence and cancer, etc. Recent studies have begun to unravel the roles of lncRNAs in tumor immunity as well. lncRNAs are involved in regulating tumor cells through downregulating tumor antigens, upregulating inhibitory signals, and recruiting immunosuppressive cells. Additionally, the functions and cell fates of immune cells (both innate and adaptive) are influenced by lncRNAs. Furthermore, lncRNAs act as messengers to mediate the communication between tumor and immune cells. In this review, we summarized the functions and mechanisms of lncRNAs in regulating tumor immunity and provided new ideas and strategies for improving the impacts of tumor immunotherapy.

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.