TY - JOUR
T1 - RelB acts as a molecular switch driving chronic inflammation in glioblastoma multiforme
AU - Waters, Michael R.
AU - Gupta, Angela S.
AU - Mockenhaupt, Karli
AU - Brown, La Shardai N.
AU - Biswas, Debolina D.
AU - Kordula, Tomasz
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85066970904&partnerID=8YFLogxK
U2 - 10.1038/s41389-019-0146-y
DO - 10.1038/s41389-019-0146-y
M3 - Article
AN - SCOPUS:85066970904
SN - 2157-9024
VL - 8
JO - Oncogenesis
JF - Oncogenesis
IS - 6
M1 - 37
ER -