RelB acts as a molecular switch driving chronic inflammation in glioblastoma multiforme

Abstract

Glioblastoma multiforme (GBM) is a primary brain tumor characterized by extensive necrosis and immunosuppressive inflammation. The mechanisms by which this inflammation develops and persists in GBM remain elusive. We identified two cytokines interleukin-1β (IL-1) and oncostatin M (OSM) that strongly negatively correlate with patient survival. We found that these cytokines activate RelB/p50 complexes by a canonical NF-κB pathway, which surprisingly drives expression of proinflammatory cytokines in GBM cells, but leads to their inhibition in non-transformed astrocytes. We discovered that one allele of the gene encoding deacetylase Sirtuin 1 (SIRT1), needed for repression of cytokine genes, is deleted in 80% of GBM tumors. Furthermore, RelB specifically interacts with a transcription factor Yin Yang 1 (YY1) in GBM cells and activates GBM-specific gene expression programs. As a result, GBM cells continuously secrete proinflammatory cytokines and factors attracting/activating glioma-associated microglia/macrophages and thus, promote a feedforward inflammatory loop.

Proteogenomics of glioblastoma associates molecular patterns with survival

“…Our analyses highlight three main mechanisms to be associated with survival: immune processes, metabolic processes, and developmental processes. We found short survival to be associated with inflammation and glycolytic metabolism, both with established roles in tumor growth and aggressiveness in GBM (Reyné s et al, 2011;Waters et al, 2019;Yeung et al, 2013). Interestingly, while NF-kB signaling and T cell immunity negatively correlate with survival and reflect a pro-tumorigenic inflammatory response, supported by a higher immune infiltration score, the WGCNA results also show a positive association between immunity and survival in the form of immunoglobulins and complement system components, suggesting a potential anti-tumorigenic immune response.…”

The Two Sides of YY1 in Cancer: A Friend and a Foe

“…It is however, not clear whether in this case YY1 forms a transcriptional repressive complex with NF-κB. Interestingly, while the YY1-RelA complex was shown to function as a transcriptional repressor (41), a complex between RelB and YY1 was shown to function as a transcriptional activator in glioblastoma multiforme (GBM) cells and promotes GBM growth (43). Likewise, YY1 interacts with a large number of factors to regulate various genes.…”

“…In this report it has been shown that miR-218 targets YY1 leading to its downregulation and impaired glioma cell proliferation. Interestingly, in glioblastoma multiforme (GBM) the NF-κB family member RelB was shown to interact with YY1 and promote expression of GBM specific genes as well as pro-inflammatory cytokines leading to infiltration of glioma associated macrophages and thus tumor progression (43). Further, YY1 was shown to confer resistance to drugs such as cisplatin in GBM (107).…”

Proteogenomics of glioblastoma associates molecular patterns with survival

“…Our analyses highlight three main mechanisms to be associated with survival: Immune processes, metabolic processes and developmental processes. We found short survival to be associated with inflammation and glycolytic metabolism, both with established roles in tumor growth and aggressiveness in GBM (Reynes et al, 2011; Waters et al, 2019; Yeung et al, 2013). Interestingly, while NF-ᴋB signaling and T cell immunity negatively correlate with survival and reflect a pro-tumorigenic inflammatory response, the WGCNA results show a positive association between immunity and survival in the form of immunoglobulins and complement system components, suggesting a potential anti-tumorigenic immune response.…”